Inhibitors of histone deacetylase

ABSTRACT

The invention relates to the inhibition of histone deacetylase. The invention provides compounds and methods for inhibiting histone deacetylase enzymatic activity. The invention also provides compositions and methods for treating cell proliferative diseases and conditions.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] This invention relates to the inhibition of histone deacetylase.More particularly, the invention relates to compounds and methods forinhibiting histone deacetylase enzymatic activity.

[0003] 2. Summary of the Related Art

[0004] In eukaryotic cells, nuclear DNA associates with histones to forma compact complex called chromatin. The histones constitute a family ofbasic proteins which are generally highly conserved across eukaryoticspecies. The core histones, termed H2A, H2B, H3, and H4, associate toform a protein core. DNA winds around this protein core, with the basicamino acids of the histones interacting with the negatively chargedphosphate groups of the DNA. Approximately 146 base pairs of DNA wraparound a histone core to make up a nucleosome particle, the repeatingstructural motif of chromatin.

[0005] Csordas, Biochem. J., 286: 23-38 (1990) teaches that histones aresubject to posttranslational acetylation of the α,ε-amino groups ofN-terminal lysine residues, a reaction that is catalyzed by histoneacetyl transferase (HAT1). Acetylation neutralizes the positive chargeof the lysine side chain, and is thought to impact chromatin structure.Indeed, Taunton et al., Science, 272: 408-411 (1996), teaches thataccess of transcription factors to chromatin templates is enhanced byhistone hyperacetylation. Taunton et al. further teaches that anenrichment in underacetylated histone H4 has been found intranscriptionally silent regions of the genome.

[0006] Histone acetylation is a reversible modification, withdeacetylation being catalyzed by a family of enzymes termed histonedeacetylases (HDACs). Grozinger et al., Proc. Natl. Acad. Sci. USA, 96:4868-4873 (1999), teaches that HDACs is divided into two classes, thefirst represented by yeast Rpd3-like proteins, and the secondrepresented by yeast Hda1-like proteins. Grozinger et al. also teachesthat the human HDAC1, HDAC2, and HDAC3 proteins are members of the firstclass of HDACs, and discloses new proteins, named HDAC4, HDAC5, andHDAC6, which are members of the second class of HDACs. Kao et al., Genes& Dev., 14: 55-66 (2000), discloses HDAC7, a new member of the secondclass of HDACs. Van den Wyngaert, FEBS, 478: 77-83 (2000) disclosesHDAC8, a new member of the first class of HDACs.

[0007] Richon et al., Proc. Natl. Acad. Sci. USA, 95: 3003-3007 (1998),discloses that HDAC activity is inhibited by trichostatin A (TSA), anatural product isolated from Streptomyces hygroscopicus, and by asynthetic compound, suberoylanilide hydroxamic acid (SAHA). Yoshida andBeppu, Exper. Cell Res., 177: 122-131 (1988), teaches that TSA causesarrest of rat fibroblasts at the G₁ and G₂ phases of the cell cycle,implicating HDAC in cell cycle regulation. Indeed, Finnin et al.,Nature, 401: 188-193 (1999), teaches that TSA and SAHA inhibit cellgrowth, induce terminal differentiation, and prevent the formation oftumors in mice. Suzuki et al., U.S. Pat. No. 6,174,905, EP 0847992, JP258863/96, and Japanese Application No. 10138957, disclose benzamidederivatives that induce cell differentiation and inhibit HDAC. Delormeet al., WO 01/38322 and PCT IB01/00683, disclose additional compoundsthat serve as HDAC inhibitors.

[0008] The molecular cloning of gene sequences encoding proteins withHDAC activity has established the existence of a set of discrete HDACenzyme isoforms. Grozinger et al., Proc. Natl. Acad. Sci. USA,96:4868-4873 (1999), teaches that HDACs may be divided into two classes,the first represented by yeast Rpd3-like proteins, and the secondrepresented by yeast Hda1-like proteins. Grozinger et al. also teachesthat the human HDAC-1, HDAC-2, and HDAC-3 proteins are members of thefirst class of HDACs, and discloses new proteins, named HDAC-4, HDAC-5,and HDAC-6, which are members of the second class of HDACs. Kao et al.,Gene & Development 14:55-66 (2000), discloses an additional member ofthis second class, called HDAC-7. More recently, Hu, E. et al. J. Bio.Chem. 275:15254-13264 (2000) discloses the newest member of the firstclass of histone deacetylases, HDAC-8. It has been unclear what rolesthese individual HDAC enzymes play.

[0009] These findings suggest that inhibition of HDAC activityrepresents a novel approach for intervening in cell cycle regulation andthat HDAC inhibitors have great therapeutic potential in the treatmentof cell proliferative diseases or conditions. To date, few inhibitors ofhistone deacetylase are known in the art. There is thus a need toidentify additional HDAC inhibitors and to identify the structuralfeatures required for potent HDAC inhibitory activity.

BRIEF SUMMARY OF THE INVENTION

[0010] The invention provides compounds and methods for treating cellproliferative diseases. The invention provides new inhibitors of histonedeacetylase enzymatic activity.

[0011] In a first aspect, the invention provides compounds that areuseful as inhibitors of histone deacetylase.

[0012] In a second aspect, the invention provides a compositioncomprising an inhibitor of histone deacetylase according to theinvention and a pharmaceutically acceptable carrier, excipient, ordiluent.

[0013] In a third aspect, the invention provides a method of inhibitinghistone deacetylase in a cell, comprising contacting a cell in whichinhibition of histone deacetylase is desired with an inhibitor ofhistone deacetylase of the invention.

[0014] The foregoing merely summarizes certain aspects of the inventionand is not intended to be limiting in nature. These aspects and otheraspects and embodiments are described more fully below.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015]FIG. 1 is a graph showing the antitumor activity of compound 106in an HCT 116 human colorectal tumor model.

[0016] FIGS. 2-11 show additional data for other compounds used in thein vivo experiment described in Assay Example 2.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0017] The invention provides compounds and methods for inhibitinghistone deacetylase enzymatic activity. The invention also providescompositions and methods for treating cell proliferative diseases andconditions. The patent and scientific literature referred to hereinestablishes knowledge that is available to those with skill in the art.The issued patents, applications, and references that are cited hereinare hereby incorporated by reference to the same extent as if each wasspecifically and individually indicated to be incorporated by reference.In the case of inconsistencies, the present disclosure will prevail.

[0018] For purposes of the present invention, the following definitionswill be used (unless expressly stated otherwise):

[0019] As used herein, the terms “histone deacetylase” and “HDAC” areintended to refer to any one of a family of enzymes that remove acetylgroups from the, -amino groups of lysine residues at the N-terminus of ahistone. Unless otherwise indicated by context, the term “histone” ismeant to refer to any histone protein, including H1, H2A, H2B, H3, H4,and H5, from any species. Preferred histone deacetylases include class Iand class II enzymes. Preferably the histone deacetylase is a humanHDAC, including, but not limited to, HDAC-1, HDAC-2, HDAC-3, HDAC-4,HDAC-5, HDAC-6, HDAC-7, and HDAC-8. In some other preferred embodiments,the histone deacetylase is derived from a protozoal or fungal source.

[0020] The terms “histone deacetylase inhibitor” and “inhibitor ofhistone deacetylase” are used to identify a compound having a structureas defined herein, which is capable of interacting with a histonedeacetylase and inhibiting its enzymatic activity. “Inhibiting histonedeacetylase enzymatic activity” means reducing the ability of a histonedeacetylase to remove an acetyl group from a histone. In some preferredembodiments, such reduction of histone deacetylase activity is at leastabout 50%, more preferably at least about 75%, and still more preferablyat least about 90%. In other preferred embodiments, histone deacetylaseactivity is reduced by at least 95% and more preferably by at least 99%.

[0021] Preferably, such inhibition is specific, i.e., the histonedeacetylase inhibitor reduces the ability of a histone deacetylase toremove an acetyl group from a histone at a concentration that is lowerthan the concentration of the inhibitor that is required to produceanother, unrelated biological effect. Preferably, the concentration ofthe inhibitor required for histone deacetylase inhibitory activity is atleast 2-fold lower, more preferably at least 5-fold lower, even morepreferably at least 10-fold lower, and most preferably at least 20-foldlower than the concentration required to produce an unrelated biologicaleffect.

[0022] For simplicity, chemical moieties are defined and referred tothroughout primarily as univalent chemical moieties (e.g., alkyl, aryl,etc.). Nevertheless, such terms are also used to convey correspondingmultivalent moieties under the appropriate structural circumstancesclear to those skilled in the art. For example, while an “alkyl” moietygenerally refers to a monovalent radical (e.g. CH₃—CH₂—), in certaincircumstances a bivalent linking moiety can be “alkyl,” in which casethose skilled in the art will understand the alkyl to be a divalentradical (e.g., —CH₂—CH₂—), which is equivalent to the term “alkylene.”(Similarly, in circumstances in which a divalent moiety is required andis stated as being “aryl,” those skilled in the art will understand thatthe term “aryl” refers to the corresponding divalent moiety, arylene.)All atoms are understood to have their normal number of valences forbond formation (i.e., 4 for carbon, 3 for N, 2 for O, and 2, 4, or 6 forS, depending on the oxidation state of the S). On occasion a moiety maydefined, for example, as (A)_(a)—B—, wherein a is 0 or 1. In suchinstances, when a is 0 the moiety is B— and when a is 1 the moiety is A—B—. Also, a number of moieties disclosed herein exist in multipletautomeric forms, all of which are intended to be encompassed by anygiven tautomeric structure.

[0023] The term “hydrocarbyl” refers to a straight, branched, or cyclicalkyl, alkenyl, or alkynyl, each as defined herein. A “C₀” hydrocarbylis used to refer to a covalent bond. Thus, “C₀-C₃-hydrocarbyl” includesa covalent bond, methyl, ethyl, propyl, and cyclopropyl.

[0024] The term “alkyl” as employed herein refers to straight andbranched chain aliphatic groups having from 1 to 12 carbon atoms,preferably 1-8 carbon atoms, and more preferably 1-6 carbon atoms, whichis optionally substituted with one, two or three substituents. Preferredalkyl groups include, without limitation, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, and hexyl. A“C₀” alkyl (as in “C₀-C₃-alkyl”) is a covalent bond (like “C₀”hydrocarbyl).

[0025] The term “alkenyl” as used herein means an unsaturated straightor branched chain aliphatic group with one or more carbon-carbon doublebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkenyl groups include,without limitation, ethenyl, propenyl, butenyl, pentenyl, and hexenyl.

[0026] The term “alkynyl” as used herein means an unsaturated straightor branched chain aliphatic group with one or more carbon-carbon triplebonds, having from 2 to 12 carbon atoms, preferably 2-8 carbon atoms,and more preferably 2-6 carbon atoms, which is optionally substitutedwith one, two or three substituents. Preferred alkynyl groups include,without limitation, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0027] An “alkylene,” “alkenylene,” or “alkynylene” group is an alkyl,alkenyl, or alkynyl group, as defined hereinabove, that is positionedbetween and serves to connect two other chemical groups. Preferredalkylene groups include, without limitation, methylene, ethylene,propylene, and butylene. Preferred alkenylene groups include, withoutlimitation, ethenylene, propenylene, and butenylene. Preferredalkynylene groups include, without limitation, ethynylene, propynylene,and butynylene.

[0028] The term “cycloalkyl” as employed herein includes saturated andpartially unsaturated cyclic hydrocarbon groups having 3 to 12 carbons,preferably 3 to 8 carbons, and more preferably 3 to 6 carbons, whereinthe cycloalkyl group additionally is optionally substituted. Preferredcycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl,cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, andcyclooctyl.

[0029] The term “heteroalkyl” refers to an alkyl group, as definedhereinabove, wherein one or more carbon atoms in the chain are replacedby a heteratom selected from the group consisting of O, S, and N.

[0030] An “aryl” group is a C₆-C₁₄ aromatic moiety comprising one tothree aromatic rings, which is optionally substituted. Preferably, thearyl group is a C₆-C₁₀ aryl group. Preferred aryl groups include,without limitation, phenyl, naphthyl, anthracenyl, and fluorenyl. An“aralkyl” or “arylalkyl” group comprises an aryl group covalently linkedto an alkyl group, either of which may independently be optionallysubstituted or unsubstituted. Preferably, the aralkyl group is(C₁-C₆)alk(C₆-C₁₀)aryl, including, without limitation, benzyl,phenethyl, and naphthylmethyl.

[0031] A “heterocyclyl” or “heterocyclic” group is a ring structurehaving from about 3 to about 8 atoms, wherein one or more atoms areselected from the group consisting of N, O, and S. The heterocyclicgroup is optionally substituted on carbon at one or more positions. Theheterocyclic group is also independently optionally substituted onnitrogen with alkyl, aryl, aralkyl, alkylcarbonyl, alkylsulfonyl,arylcarbonyl, arylsulfonyl, alkoxycarbonyl, aralkoxycarbonyl, or onsulfur with oxo or lower alkyl. Preferred heterocyclic groups include,without limitation, epoxy, aziridinyl, tetrahydrofuranyl, pyrrolidinyl,piperidinyl, piperazinyl, thiazolidinyl, oxazolidinyl, oxazolidinonyl,and morpholino. In certain preferred embodiments, the heterocyclic groupis fused to an aryl, heteroaryl, or cycloalkyl group. Examples of suchfused heterocyles include, without limitation, tetrahydroquinoline anddihydrobenzofuran. Specifically excluded from the scope of this term arecompounds having adjacent annular O and/or S atoms.

[0032] As used herein, the term “heteroaryl” refers to groups having 5to 14 ring atoms, preferably 5, 6, 9, or 10 ring atoms; having 6, 10, or14 π electrons shared in a cyclic array; and having, in addition tocarbon atoms, from one to three heteroatoms per ring selected from thegroup consisting of N, O, and S. A “heteroaralkyl” or “heteroarylalkyl”group comprises a heteroaryl group covalently linked to an alkyl group,either of which is independently optionally substituted orunsubstituted. Preferred heteroalkyl groups comprise a C₁-C₆ alkyl groupand a heteroaryl group having 5, 6, 9, or 10 ring atoms. Specificallyexcluded from the scope of this term are compounds having adjacentannular O and/or S atoms. Examples of preferred heteroaralkyl groupsinclude pyridylmethyl, pyridylethyl, pyrrolylmethyl, pyrrolylethyl,imidazolylmethyl, imidazolylethyl, thiazolylmethyl, and thiazolylethyl.Specifically excluded from the scope of this term are compounds havingadjacent annular O and/or S atoms.

[0033] An “arylene,” “heteroarylene,” or “heterocyclylene” group is anaryl, heteroaryl, or heterocyclyl group, as defined hereinabove, that ispositioned between and serves to connect two other chemical groups.

[0034] Preferred heterocyclyls and heteroaryls include, but are notlimited to, acridinyl, azocinyl, benzimidazolyl, benzofuranyl,benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzthiazolyl,benztriazolyl, benztetrazolyl, benzisoxazolyl, benzisothiazolyl,benzimidazolinyl, carbazolyl, 4aH-carbazolyl, carbolinyl, chromanyl,chromenyl, cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl, isochromanyl,isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl, isothiazolyl,isoxazolyl, methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl, quinoxalinyl,quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl.

[0035] As employed herein, when a moiety (e.g., cycloalkyl, hydrocarbyl,aryl, heteroaryl, heterocyclic, urea, etc.) is described as “optionallysubstituted” it is meant that the group optionally has from one to four,preferably from one to three, more preferably one or two, non-hydrogensubstituents. Suitable substituents include, without limitation, halo,hydroxy, oxo (e.g., an annular —CH— substituted with oxo is —C(O)—)nitro, halohydrocarbyl, hydrocarbyl, aryl, aralkyl, alkoxy, aryloxy,amino, acylamino, alkylcarbamoyl, arylcarbamoyl, aminoalkyl, acyl,carboxy, hydroxyalkyl, alkanesulfonyl, arenesulfonyl, alkanesulfonamido,arenesulfonamido, aralkylsulfonamido, alkylcarbonyl, acyloxy, cyano, andureido groups. Preferred substituents, which are themselves not furthersubstituted (unless expressly stated otherwise) are:

[0036] (a) halo, cyano, oxo, carboxy, formyl, nitro, amino, amidino,guanidino,

[0037] (b) C₁-C₅ alkyl or alkenyl or arylalkyl imino, carbamoyl, azido,carboxamido, mercapto, hydroxy, hydroxyalkyl, alkylaryl, arylalkyl,C₁-C₈ alkyl, C_(1-C) ₈ alkenyl, C₁-C₈ alkoxy, C₁-C₈ alkoxycarbonyl,aryloxycarbonyl, C₂-C₈ acyl, C₂-C₈ acylamino, C₁-C₈ alkylthio,arylalkylthio, arylthio, C₁-C₈ alkylsulfinyl, arylalkylsulfinyl,arylsulfinyl, C₁-C₈ alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl,C₀-C₆ N-alkyl carbamoyl, C₂-C₁₅ N,N-dialkylcarbamoyl, C₃-C₇ cycloalkyl,aroyl, aryloxy, arylalkyl ether, aryl, aryl fused to a cycloalkyl orheterocycle or another aryl ring, C₃-C₇ heterocycle, or any of theserings fused or spiro-fused to a cycloalkyl, heterocyclyl, or aryl,wherein each of the foregoing is further optionally substituted with onemore moieties listed in (a), above; and

[0038] (c) —(CH₂)_(s)—NR³⁰R³¹, wherein s is from 0 (in which case thenitrogen is directly bonded to the moiety that is substituted) to 6, andR³⁰ and R³¹ are each independently hydrogen, cyano, oxo, carboxamido,amidino, C₁-C₈ hydroxyalkyl, C₁-C₃ alkylaryl, aryl-C₁-C₃ alkyl, C₁-C₈alkyl, C₁-C₈ alkenyl, C₁-C₈ alkoxy, C₁-C₈ alkoxycarbonyl,aryloxycarbonyl, aryl-C₁-C₃ alkoxycarbonyl, C₂-C₈ acyl, C₁-C₈alkylsulfonyl, arylalkylsulfonyl, arylsulfonyl, aroyl, aryl, cycloalkyl,heterocyclyl, or heteroaryl, wherein each of the foregoing is furtheroptionally substituted with one more moieties listed in (a), above; or

[0039] R³⁰ and R³¹ taken together with the N to which they are attachedform a heterocyclyl or heteroaryl, each of which is optionallysubstituted with from 1 to 3 substituents from (a), above.

[0040] In addition, substituents on cyclic moieties (i.e., cycloalkyl,heterocyclyl, aryl, heteroaryl) include 5-6 membered mono- and 10-12membered bi-cyclic moieties fused to the parent cyclic moiety to form abi- or tricyclic fused ring system. For example, an optionallysubstituted phenyl includes the following:

[0041] A “halohydrocarbyl” is a hydrocarbyl moiety in which from one toall hydrogens have been replaced with one or more halo.

[0042] The term “halogen” or “halo” as employed herein refers tochlorine, bromine, fluorine, or iodine. As herein employed, the term“acyl” refers to an alkylcarbonyl or arylcarbonyl substituent. The term“acylamino” refers to an amide group attached at the nitrogen atom(i.e., R—CO—NH—). The term “carbamoyl” refers to an amide group attachedat the carbonyl carbon atom (i.e., NH₂—CO—). The nitrogen atom of anacylamino or carbamoyl substituent is additionally substituted. The term“sulfonamido” refers to a sulfonamide substituent attached by either thesulfur or the nitrogen atom. The term “amino” is meant to include NH₂,alkylamino, arylamino, and cyclic amino groups. The term “ureido” asemployed herein refers to a substituted or unsubstituted urea moiety.

[0043] The term “radical” as used herein means a chemical moietycomprising one or more unpaired electrons.

[0044] A moiety that is substituted is one in which one or morehydrogens have been independently replaced with another chemicalsubstituent. As a non-limiting example, substituted phenyls include2-flurophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl,2-fluor-3-propylphenyl. As another non-limiting example, substitutedn-octyls include 2,4 dimethyl-5-ethyl-octyl and 3-cyclopentyl-octyl.Included within this definition are methylenes (—CH₂—) substituted withoxygen to form carbonyl —CO—).

[0045] An “unsubstituted” moiety as defined above (e.g., unsubstitutedcycloalkyl, unsubstituted heteroaryl, etc.) means that moiety as definedabove that does not have any of the optional substituents for which thedefinition of the moiety (above) otherwise provides. Thus, for example,while an “aryl” includes phenyl and phenyl substituted with a halo,“unsubstituted aryl” does not include phenyl substituted with a halo.

[0046] Preferred embodiments of a particular genus of compounds of theinvention include combinations of preferred embodiments. For example,paragraph [0042] identifies a preferred Ay¹ and paragraph [0046]identifies preferred Ar¹ (both for compound (1) of paragraph [0041]).Thus, another preferred embodiment includes those compounds of formula(1) in paragraph [0041] in which Ay¹ is as defined in paragraph [0042]and Ar¹ is as defined in paragraph [0046].

[0047] Compounds

[0048] In a first aspect, the invention provides novel inhibitors ofhistone deacetylase. In a first embodiment, the novel inhibitors ofhistone deacetylase are represented by formula (1):

[0049] and pharmaceutically acceptable salts thereof, wherein

[0050] R³ and R⁴ are independently selected from the group consisting ofhydrogen, L¹, Cy¹, and —L¹—Cy¹, wherein

[0051] L¹ is C₁-C₆ alkyl, C₂-C₆ heteroalkyl, or C₃-C₆ alkenyl; and

[0052] Cy¹ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each ofwhich optionally is substituted, and each of which optionally is fusedto one or more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings, each of whichrings optionally is substituted; or

[0053] R³ and R⁴ are taken together with the adjacent nitrogen atom toform a 5-, 6-, or 7-membered ring, wherein the ring atoms areindependently selected from the group consisting of C, O, S, and N, andwherein the ring optionally is substituted, and optionally forms part ofa bicyclic ring system, or optionally is fused to one or more aryl orheteroaryl rings, or to one or more saturated or partially unsaturatedcycloalkyl or heterocyclic rings, each of which rings and ring systemsoptionally is substituted;

[0054] Y¹ is selected from the group consisting of —N(R¹)(R²),—CH₂—C(O)—N(R¹)(R²), halogen, and hydrogen, wherein

[0055] R¹ and R² are independently selected from the group consisting ofhydrogen, L¹, Cy¹, and —L¹—Cy¹, wherein

[0056] L¹ is C₁-C₆ alkyl, C₂-C₆ heteroalkyl, or C₃-C₆ alkenyl; and

[0057] Cy¹ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each ofwhich optionally is substituted, and each of which optionally is fusedto one or more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings, each of whichrings optionally is substituted; or

[0058] R¹ and R² are taken together with the adjacent nitrogen atom toform a 5-, 6-, or 7-membered ring, wherein the ring atoms areindependently selected from the group consisting of C, O, S, and N, andwherein the ring optionally is substituted, and optionally may form partof a bicyclic ring system, or optionally is fused to one or more aryl orheteroaryl rings, or to one or more saturated or partially unsaturatedcycloalkyl or heterocyclic rings, each of which rings and ring systemsoptionally is substituted;

[0059] Y² is a chemical bond or N(R⁰), where R⁰ is selected from thegroup consisting of hydrogen, alkyl, aryl, aralkyl, and acyl;

[0060] Ak¹ is C₁-C₆ alkylene, C₁-C₆-heteroalkylene (preferably, in whichone —CH₂— is replaced with —NH—, and more preferably —NH—CH₂—), C₂-C₆alkenylene or C₂-C₆ alkynylene;

[0061] Ar¹ is arylene or heteroarylene, either of which optionally issubstituted; and

[0062] Z¹ is selected from the group consisting of

[0063] wherein Ay¹ is aryl or heteroaryl, which optionally issubstituted.

[0064] Preferably in the compounds according to paragraph [0041], Ay¹ isphenyl or thienyl, each substituted with —OH or —NH₂.

[0065] More preferably in the compounds according to paragraph [0041],Ay¹ is optionally amino- or hydroxy-substituted phenyl or thienyl,wherein the amino or hydroxy substituent is preferably ortho to thenitrogen to which Ay² is attached.

[0066] More preferably in the compounds according to paragraph [0041],Ay¹ is ortho aniline, ortho phenol, 3-amino-2-thienyl, or3-hydroxy-2-thienyl, and tautomers thereof.

[0067] In some preferred embodiments of the compounds according toparagraph [0041], Z¹ is

[0068] In some preferred embodiments of the compounds according toparagraph [0041], Ar¹ is phenylene. In some embodiments, Ak¹ isalkylene, preferably methylene. In some preferred embodiments, Y² is—NH—. In some preferred embodiments, Y¹ is —N(R¹)(R²) or—CH₂—C(O)—N(R¹)(R²).

[0069] In some embodiments of the compounds according to paragraph[0041], R¹ and R² are each independently selected from the groupconsisting of hydrogen, L¹, Cy¹, and —L¹—Cy¹. In some embodiments, R¹and/or R² is hydrogen. In other embodiments, R¹ and/or R² is alkyl oralkenyl, preferably allyl. In still other embodiments, R¹ and/or R² isaryl, heteroaryl, aralkyl, or heteroaralkyl, the rings of each of whichoptionally is substituted and optionally is fused to one or more arylrings. Some preferred aryl, heteroaryl, aralkyl, and heteroaralkylgroups comprise a phenyl, pyridyl, or pyrrolyl ring. In still otherembodiments, R¹ and/or R² is cycloalkyl, e.g., cyclopropyl, cyclopentyl,or cyclohexyl, which optionally is substituted and optionally is fusedto one or more aryl rings.

[0070] In some embodiments of the compounds according to paragraph[0041], R³ and R⁴ are each independently selected from the groupconsisting of hydrogen, L¹, Cy¹, and —L¹—Cy¹. In some embodiments, R³and/or R⁴ is hydrogen. In other embodiments, R³ and/or R⁴ is alkyl oralkenyl, preferably allyl. In still other embodiments, R³ and/or R⁴ isaryl, heteroaryl, aralkyl, or heteroaralkyl, the rings of each of whichoptionally is substituted and optionally is fused to one or more arylrings. Some preferred aryl, heteroaryl, aralkyl, and heteroaralkylgroups comprise a phenyl, pyridyl, or pyrrolyl ring. In still otherembodiments, R³ and/or R⁴ is cycloalkyl, e.g., cyclopropyl, cyclopentyl,or cyclohexyl, which optionally is substituted and optionally is fusedto one or more aryl rings.

[0071] As set forth above, L¹ is C₁-C₆ alkyl, C₂-C₆ heteroalkyl, orC₃-C₆ alkenyl. However, one skilled in the art will understand that whenL¹ is not a terminal group, then L¹ is C₁-C₆ alkylene, C₂-C₆heteroalkylene, or C₃-C₆ alkenylene. In some embodiments, L¹ isalkylene, preferably methylene or ethylene. In other embodiments, L¹ isalkenyl, preferably allyl. In some embodiments, Cy¹is the radical of aheterocyclic group including, without limitation, piperidine,pyrrolidine, piperazine, and morpholine, each of which optionally issubstituted and optionally is fused to one or more aryl rings. In otherembodiments Cy¹ is cycloalkyl, e.g., cyclopropyl, cyclopentyl, orcyclohexyl. In still other embodiments, Cy¹ is aryl or heteroaryl, e.g.,phenyl, pyridyl, or pyrrolyl, each of which optionally is substitutedand optionally is fused to one or more aryl rings. In some embodiments,Cy¹ is fused to one or two benzene rings. In some embodiments, Cy¹ hasbetween one and about five substituents selected from the groupconsisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, and halo. Examples of preferredsubstituents include methyl, methoxy, and fluoro.

[0072] In some embodiments of the compounds according to paragraph[0041], R¹ and R² and/or R³ and R⁴ are taken together with the adjacentnitrogen atom to form a 5- or 6-membered ring, wherein the ring atomsare independently selected from the group consisting of C, O, and N, andwherein the ring optionally is substituted, and optionally is fused toone or more aryl rings. In some preferred embodiments, R¹ and R² and/orR³ and R⁴ are taken together with the adjacent nitrogen atom to form aring such as, for example, pyrrolidine, piperidine, piperazine, andmorpholine, wherein the ring optionally is substituted, and optionallyis fused to an aryl ring. In some embodiments, the ring comprising R¹and R² or R³ and R⁴ is fused to a benzene ring. In some embodiments, thering comprising R¹ and R² or R³ and R⁴ has a substituent comprising anaryl or cycloalkyl ring, either of which optionally is substituted andoptionally is fused to a cycloalkyl, aryl, heteroaryl, or heterocyclicring. Preferred substituents include, without limitation, phenyl,phenylmethyl, and phenylethyl, the phenyl ring of which optionally isfused to a cycloalkyl, aryl, or heterocyclic ring.

[0073] In a preferred embodiment, the HDAC inhibitors of the inventioncomprise compounds of formula 1(a):

[0074] and pharmaceutically acceptable salts thereof, wherein

[0075] J is C₁-C₃-hydrocarbyl, —N(R²⁰)—, —N(R²⁰)—CH₂—, —O—, or —O—CH₂—;

[0076] R²⁰ is —H or —Me;

[0077] X and Y are independently selected from —NH₂, cycloalkyl,heterocyclyl, aryl, heteroaryl, and A—(C₁-C₆-alkyl)_(n)—B—;

[0078] A is H, C₁-C₆-alkyloxy, cycloalkyl, heterocyclyl, aryl, orheteroaryl;

[0079] B is —NH—, —O—, or a direct bond; and

[0080] n is 0 (in which case A is directly bonded to B) or 1.

[0081] Preferably in the compounds according to paragraph [0051], A isphenyl optionally substituted with one or more moieties selected fromhalo (preferably chloro) and methoxy, and B is —NH—. In anotherpreferred embodiment, A is selected from cyclopropyl, pyridinyl, andindanyl.

[0082] Preferably in the compounds according to paragraph [0051], J is—NH—CH₂—, —O—CH₂—, —N(CH₃)—CH₂—, —CH═CH—, or —CH₂—CH₂—.

[0083] Preferably in the compounds according to paragraph [0051], R²⁰ is—H.

[0084] In the compounds according to paragraph [0051] X is preferablyselected from

—OMe,

—NH₃

and

[0085] and Y is preferably selected from —NH₂,

n-BuNH, MeOCH₂CH₂NH,

—H Me —OMe CH₃(CH₂)₃NH— and CH₃O(CH₂)₂—NH—.

[0086] In a more preferred embodiment of the compounds according toparagraph [0051], the HDAC inhibitors of the invention comprise thefollowing compounds of formula 1 a: Cpd J X Y 204 —NH—

—NH₂ 207 —OCH₂—

—NH₂ 210 —-NHCH₂—

—H 212 —NHCH₂— —OMe 214 —NHCH₂—

—OMe 216

—Me 218 —NHCH₂—

—Me 220 —CH═CH— —NH₂ —NH₂— 223 —CH═CH—

—NH₂ 224 —CH₂CH₂— —NH₂ —NH₂ 470 —NHCH₂—

NH₂ 471 —NHCH₂—

472 —NHCH₂—

473 —NHCH₂—

n-BuNH 474 —NHCH₂—

MeO(CH2)₂NH 475 —NHCH₂—

476 —NHCH₂—

477 —NHCH₂—

478 —NHCH₂—

479 —NHCH₂—

480 —NHCH₂—

481 —NHCH₂—

482 —NHCH₂—

483 —NHCH₂—

Me 484 —NHCH₂—

NH₂ and 485 —NHCH₂—

[0087] In a second aspect, the novel histone deacetylase inhibitors ofthe invention are represented by formula (2):

[0088] and pharmaceutically acceptable salts thereof, wherein

[0089] Cy² is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each ofwhich is optionally substituted and each of which is optionally fused toone or more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings, each of whichrings is optionally substituted;

[0090] X¹ is selected from the group consisting of a covalent bond,M¹—L²—M¹, and L²—M²—L² wherein

[0091] L², at each occurrence, is independently selected from the groupconsisting of a chemical bond, C₁-C₄ alkylene, C₂-C₄ alkenylene, andC₂-C₄ alkynylene, provided that L² is not a chemical bond when X¹ isM¹—L²—M¹;

[0092] M¹, at each occurrence, is independently selected from the groupconsisting of —O—, —N(R⁷)—, —S—, —S(O)—, S(O)₂—, —S(O)₂N(R⁷)—,—N(R⁷)—S(O)₂—, —C(O)—, —C(O)—, NH—C(O)—NH—, —NH—C(O)—O— and —O—C(O)—NH—,wherein R⁷ is selected from the group consisting of hydrogen, alkyl,aryl, aralkyl, acyl, heterocyclyl, and heteroaryl; and

[0093] M² is selected from the group consisting of M¹, heteroarylene,and heterocyclylene, either of which rings optionally is substituted;

[0094] Ar² is arylene or heteroarylene, each of which is optionallysubstituted;

[0095] R⁵ and R⁶ are independently selected from the group consisting ofhydrogen, alkyl, aryl, and aralkyl;

[0096] q is 0 or 1; and

[0097] Ay² is a 5-6 membered cycloalkyl, heterocyclyl, or heteroarylsubstituted with an amino or hydroxy moiety (preferably these groups areortho to the amide nitrogen to which Ay² is attached) and furtheroptionally substituted;

[0098] provided that when Cy² is naphthyl, X¹ is —CH₂—, Ar² is phenyl,R⁵ and R⁶ are H, and q is 0 or 1, Ay² is not phenyl or o-hydroxyphenyl.

[0099] In a preferred embodiment of the compounds according to paragraph[0057], when Ay² is o-phenol optionally substituted by halo, nitro, ormethyl, Ar² is optionally substituted phenyl, X¹ is —O—, —CH₂—, —S—,—S—CH₂—, —S(O)—, —S(O)₂—, —C(O)—, or —OCH₂—, then Cy² is not optionallysubstituted phenyl or naphthyl.

[0100] In another preferred embodiment of the compounds according toparagraph [0057], when Ay² is o-anilinyl optionally substituted by halo,C₁-C₆-alkyl, C₁-C₆-alkoxy or —NO₂, q is O, Ar² is phenyl, and X¹ is—CH₂—, then Cy² is not substituted pyridone (which substituents of thepyridone are not limited to substituents described herein).

[0101] In another preferred embodiment of the compounds according toparagraph [0057], when X¹ is —CH₂—, Ar² is optionally substitutedphenyl, q is 1, and R⁶ is H, then Cy² is not optionally substitutedimidazole.

[0102] In another preferred embodiment of the compounds according toparagraph [0057], when Ar² is amino or hydroxy substituted phenyl, X¹ isC₀-C₈-alkyl-X^(1a)—C₀-C₈-alkyl, wherein X^(1a) is —CH₂—, —O—, —S—, —NH—,—C(O)—, then Cy² is not optionally substituted naphthyl or di- or-tetrahydronaphthalene.

[0103] In another preferred embodiment of the compounds according toparagraph [0057], when Ay² is o-phenol, Ar² is substituted phenyl, X¹ is—O—, —S—, —CH₂—, —O—CH₂—, —S—CH₂—, or —C(O)—, and R⁵ and R⁶ are H, thenCy² is not optionally substituted naphthyl.

[0104] In another preferred embodiment of the compounds according toparagraph [0057], when Ay² is o-anilinyl, q is O, Ar² is unsubstitutedphenyl, X¹ is —CH₂—, then Cy² is not substituted6-hydroimidazolo[5,4-d]pyridazin-7-one-1-yl or substituted6-hydroimidazolo[5,4-d]pyridazine-7-thione-1-yl.

[0105] Preferably in the compounds according to paragraph [0057], Ay² isphenyl or thienyl, each substituted with —OH or —NH₂.

[0106] More preferably in the compounds according to paragraph [0057],Ay² is optionally amino- or hydroxy-substituted phenyl or thienyl,wherein the amino or hydroxy substituent is preferably ortho to thenitrogen to which Ay² is attached.

[0107] More preferably in the compounds according to paragraph [0057],Ay² is ortho aniline, ortho phenol, 3-amino-2-thienyl, or3-hydroxy-2-thienyl, and tautomers thereof.

[0108] In a another embodiment, the novel histone deacetylase inhibitorsof the invention are those according to paragraph [0057] wherein

[0109] q is 1;

[0110] M¹, at each occurrence, is selected from the group consisting of—N(R⁷)—, —S—, —C(O)—NH—, and —O—C(O)—NH—, where R⁷ is selected from thegroup consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; and

[0111] Ay² is anilinyl, which optionally is substituted.

[0112] In some preferred embodiments of the compounds according toparagraph [0067], the —NH₂ group of Ay² is in an ortho position withrespect to the nitrogen atom to which Ay² is attached. In someembodiments, R⁵ and R⁶ are independently selected from the groupconsisting of hydrogen and C₁-C₄ alkyl. In some preferred embodiments,R⁵ and R⁶ are hydrogen.

[0113] In some embodiments of the compounds according to paragraph[0067], Ar² has the formula

[0114] wherein G, at each occurrence, is independently N or C, and Coptionally is substituted. In some preferred embodiments, Ar² has theformula

[0115] In some preferred embodiments of the compounds according toparagraph [0069], Ar² is selected from the group consisting ofphenylene, pyridylene, pyrimidylene, and quinolylene.

[0116] In some embodiments of the compounds according to paragraph[0067], X¹ is a chemical bond. In some embodiments, X¹ is L²—M²—L², andM² is selected from the group consisting of —NH—, —N(CH₃)—, —S—,—C(O)—N(H)—, and —O—C(O)—N(H)—. In some embodiments, X¹ is L²—M²—L²,where at least one occurrence of L² is a chemical bond. In otherembodiments, X¹ is L²—M²—L², where at least one occurrence of L² isalkylene, preferably methylene. In still other embodiments, X¹ isL²—M²—L², where at least one occurrence of L² is alkenylene. In someembodiments, X¹ is M¹—L²—M¹ and M¹ is selected from the group consistingof —NH—, —N(CH₃)—, —S—, and —C(O)—N(H)—.

[0117] In some embodiments of the compounds according to paragraph[0067], Cy² is aryl or heteroaryl, e.g., phenyl, pyridyl, imidazolyl, orquinolyl, each of which optionally is substituted. In some embodiments,Cy² is heterocyclyl, e.g.,

[0118] each of which optionally is substituted and optionally is fusedto one or more aryl rings. In some embodiments, Cy² has from one andthree substituents independently selected from the group consisting ofalkyl, alkoxy, amino, nitro, halo, haloalkyl, and haloalkoxy. Examplesof preferred substituents include methyl, methoxy, fluoro,trifluoromethyl, trifluoromethoxy, nitro, amino, aminomethyl, andhydroxymethyl.

[0119] In a preferred embodiment of the compounds of paragraph [0057],the invention comprises compounds of structural formula (2a):

[0120] and pharmaceutically acceptable salts thereof, wherein

[0121] Ar^(a) is phenyl or thienyl;

[0122] R⁶ is H, or C₁-C₆-alkyl (preferably —CH₃);

[0123] Y and Z are independently —CH═ or —N═;

[0124] W is halo, (V′—L⁴)_(t)—V—L³—;

[0125] L³ is a direct bond, —C₁-C₆-hydrocarbyl,—(C₁-C₃-hydrocarbyl)_(m1)—X′—(C₁-C₃-hydrocarbyl)_(m2),—NH—(C₀-C₃-hydrocarbyl), (C₁-C₃-hydrocarbyl)-NH—, or—NH—(C₁-C₃-hydrocarbyl)-NH—;

[0126] m1 and m2 are independently 0 or 1;

[0127] X′ is —N(R²¹)—, —C(O)N(R²¹)—, N(R²¹)C(O)—, —O—, or —S—;

[0128] R²¹ is —H, V″—(C₁-C₆-hydrocarbyl)_(c);

[0129] L⁴ is (C₁-C₆-hydrocarbyl)_(a)—M—(C₁-C₆-hydrocarbyl)_(b);

[0130] a and b are independently 0 or 1;

[0131] M is —NH—, —NHC(O)—, —C(O)NH—, —C(O)—, —SO₂—, —NHSO₂—, or —SO₂NH—

[0132] V, V′, and V″ are independently selected from cycloalkyl,heterocyclyl, aryl, and heteroaryl;

[0133] t is 0 or 1;

[0134] or W, the annular C to which it is bound, and Y together form amonocyclic cycloalkyl, heterocyclyl, aryl, or heteroaryl; and

[0135] wherein the

and Ar^(a) rings are optionally further substituted with from 1 to 3substituents independently selected from methyl, hydroxy, methoxy, halo,and amino.

[0136] In a preferred embodiment of the compound according to paragraph[0073]:

[0137] Y and Z are —CH═ and R⁶ is H;

[0138] W is V—L³;

[0139] L³ is —NH—CH— or —CH—NH—;

[0140] V is phenyl optionally substituted with from 1 to 3 moietiesindependently selected from halo, hydroxy, C₁-C₆-hydrocarbyl,C₁-C₆-hydrocarbyl-oxy or -thio (particularly methoxy or methylthio),wherein each of the hydrocarbyl moieties are optionally substituted withone or more moieties independently selected from halo, nitroso, amino,sulfonamido, and cyano; and

[0141] Ar^(a) is phenyl and the amino moieties to which it is bound areortho to each other.

[0142] In some preferred embodiments of the compound according toparagraph [0073], V is an optionally substituted ring moiety selectedfrom:

[0143] In another preferred embodiment of the compounds according toparagraph [0073], W is selected from:

[0144] In another preferred embodiment of the compounds according toparagraph [0073], the

and Ar^(a) rings are not further substituted.

[0145] In a particularly preferred embodiment of the compounds accordingto paragraph [0073], the compounds of the invention are selected fromthe following, in which, unless expressly displayed otherwise, Ar^(a) isphenyl (and, preferably, the amide nitrogen and the amino nitrogen boundto Ar^(a) are ortho to each other): Cpd W Y Z R⁶ 481

CH CH H 484

492

CH CH H 493

CH CH H 494

CH CH H 495

CH CH H 496

CH CH H 497

CH CH H 498

CH CH H 499

CH CH H 500

CH CH H 501

CH CH H 502

CH CH H 503

CH CH H 504

CH CH H 505

CH CH H 506

CH CH H 507

CH CH H 508

CH CH H 509

CH CH H 510

CH CH H 511

CH CH H 512

CH CH H 516 Br CH CH CH₃ 517

CH CH CH₃ 518

CH CH CH₃ 519

CH CH H 520

CH CH H 521

N CH H 522

N CH H 523

CH CH H 524

N CH H 525

N CH H 526

CH CH H 527

CH CH H 528

CH CH H 529

CH CH H 530

CH CH H 531

CH CH H 532

CH CH H 533

CH CH H 534

CH CH H 535

CH CH H 536

CH CH H 537

CH CH H 538

CH CH H 539

CH CH H 540

CH CH H 541

CH CH H 542

CH CH H 543

CH CH H 544

CH CH H 545

CH CH H 546

CH CH H 547

CH CH H 548

CH CH H 549

CH CH H 550

CH CH H 551

CH CH H 552

CH CH H 553

CH CH H 554

CH CH H 555

CH CH H 556

CH CH H 557

CH CH H 558

CH CH H 559

CH CH H 560

561

562

CH CH H 563

CH CH H 564

565

CH CH H 566

CH CH H 567

568

569

CH CH H 570

[0146] In a preferred embodiment of the compounds according to paragraph[0057], the invention comprises compounds of the formula (2b):

[0147] and pharmaceutically acceptable salts thereof, wherein

[0148] Ay² is phenyl or thienyl, each substituted at the ortho positionwith —NH₂ or —OH and each further optionally substituted with one tothree substituents independently selected from —NH₂, —OH, and halo;

[0149] q is 0 or 1;

[0150] X¹ is selected from —CH₂—, —NH—CH₂—, and —S—CH₂—;

[0151] Cy² is monocyclic or fused bicyclic aryl or heteroaryl optionallysubstituted with one to three substituents selected from CH₃—, CH₃O—,phenyl optionally substituted with one to three CH₃O—, morphylinyl,morphylinyl-C₁-C₃-alkoxy, cyano, and CH₃C(O)NH—;

[0152] provided that when Cy² is naphthyl, X¹ is —CH₂—, and q is 0 or 1,Ay² is not o-hydroxyphenyl.

[0153] Preferably in the compounds according to paragraph [0079], Ay² isselected from:

[0154] Preferably in the compounds according to paragraph [0079], Cy² isphenyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl,tetrahydroquinozolinyl, or 1,3-dihydroquinazoline-2,4-dione, eachoptionally substituted with one to three CH₃O—. More preferably, Cy² isphenyl substituted with one to three CH₃O—.

[0155] In a third embodiment, the novel inhibitors of histonedeacetylase are represented by formula (3):

[0156] and pharmaceutical salts thereof, wherein

[0157] Ar³ is arylene or heteroarylene, either of which optionally issubstituted;

[0158] Cy³ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each ofwhich optionally is substituted, and each of which optionally is fusedto one or more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings, each of whichrings optionally is substituted;

[0159] provided that when Cy³ is a cyclic moiety having —C(O)—, —C(S)—,—S(O)—, or —S(O)₂— in the ring, then Cy³ is not additionally substitutedwith a group comprising an aryl or heteroaryl ring; and

[0160] X² is selected from the group consisting of a chemical bond, L³,W¹—L³, L³—W¹, W¹—L³—W¹, and L³—W¹ 13 L³, wherein

[0161] W¹, at each occurrence, is S, O, or N(R⁹), where R⁹ is selectedfrom the group consisting of hydrogen, alkyl, aryl, and aralkyl; and

[0162] L³ is C₁-C₄ alkylene, C₂-C₄ alkenylene, or C₂-C₄ alkynylene;

[0163] provided that X² does not comprise a —C(O)—, —C(S)—, —S(O)—, or—S(O)₂— group; and further provided that when Cy³ is pyridine, then X²is L³, W¹—L³, or L³—W¹.

[0164] Preferably, Ar³ has the structure:

[0165] wherein Q, at each occurrence, is independently N or C, and Coptionally is substituted.

[0166] Preferably in the compounds according to paragraph [0082], X² isselected from the group consisting of L³, W¹—L³, L³—W¹, W¹—L³—W¹, andL³—W¹—L³.

[0167] Preferably in the compounds according to paragraph [0082], whenX² is a chemical bond, then Ar³ is not

[0168] and Cy³ is not the radical of a substituted or unsubstituteddiazepine or benzofuran.

[0169] In some embodiments of the compounds according to paragraph[0082], Q at each occurrence is C(R⁸), where R⁸ is selected from thegroup consisting of hydrogen, alkyl, aryl, aralkyl, alkoxy, amino,nitro, halo, haloalkyl, and haloalkoxy. In some other embodiments, fromone to about three variables Q are nitrogen. In some preferredembodiments, Ar³ is selected from the group consisting of phenylene,pyridylene, thiazolylene, and quinolylene.

[0170] In some embodiments of the compounds according to paragraph[0082], X² is a chemical bond. In other embodiments, X² is a non-cyclichydrocarbyl. In some such embodiments, X² is alkylene, preferablymethylene or ethylene. In other such embodiments, X² is alkenylene oralkynylene. In still other such embodiments, one carbon in thehydrocaryl chain is replaced with —NH— or —S—. In some preferredembodiments, X² is W¹—L³—W¹ and W¹ is —NH— or —N(CH₃)—.

[0171] In some embodiments of the compounds according to paragraph[0082], Cy³ is cycloalkyl, preferably cyclohexyl. In other embodiments,Cy³ is aryl or heteroaryl, e.g., phenyl, pyridyl, pyrimidyl, imidazolyl,thiazolyl, oxadiazolyl, quinolyl, or fluorenyl, each of which optionallyis substituted and optionally is fused to one or more aryl rings. Insome embodiments, the cyclic moiety of Cy³ is fused to a benzene ring.In some embodiments, Cy³ has from one to three substituentsindependently selected from the group consisting of alkyl, alkoxy, aryl,aralkyl, amino, halo, haloalkyl, and hydroxyalkyl. Examples of preferredsubstituents include methyl, methoxy, fluoro, trifluoromethyl, amino,nitro, aminomethyl, hydroxymethyl, and phenyl. Some other preferredsubstituents have the formula —K¹—N(H)(R¹⁰), wherein

[0172] K¹ is a chemical bond or C₁-C₄ alkylene;

[0173] R¹⁰ is selected from the group consisting of Z′ and —Ak²—Z′,wherein

[0174] Ak² is C₁-C₄ alkylene; and

[0175] Z′ is cycloalkyl, aryl, heteroaryl, or heterocyclyl, each ofwhich optionally is substituted, and each of which optionally is fusedto one or more aryl or heteroaryl rings, or to one or more saturated orpartially unsaturated cycloalkyl or heterocyclic rings.

[0176] Examples of such preferred substituents according to paragraph[0088] include

[0177] In some embodiments of the compounds according to paragraph[0082], Cy³ is heterocyclyl, e.g.,

[0178] each of which optionally is substituted and optionally is fusedto one or more aryl rings. In some embodiments, the heterocycle of Cy³is fused to a benzene ring.

[0179] Preferably in the compounds of paragraph [0082], when Ar⁴ isquinoxalinylene, then X³ is not —CH(OH)—.

[0180] In another preferred embodiment, Ar³ is

[0181] wherein X is —CH₂—, —NH—, O, or S. Preferably Ar³ is

[0182] and X is S or O.

[0183] In a preferred embodiment, the novel histone deacetylaseinhibitors of the invention are those according to paragraph [0057]wherein

[0184] Ay² is ortho-anilinyl;

[0185] q is O; and

[0186] X¹ is M¹—L²—M¹ or L²—M²—L².

[0187] In a preferred embodiment of the compounds according to paragraph[0093], Ar² is aryl or heteroaryl; and Cy²—X¹— is collectively selectedfrom the group consisting of

[0188] a) A₁—L₁—B¹—, wherein A₁ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁ is —(CH₂)₀₋₁NH(CH₂)₀₋₁—, —NHC(O)—, or —NHCH₂—;and wherein B₁ is phenyl or a covalent bond;

[0189] b) A₂—L₂—B₂—, wherein A₂ is CH₃(C═CH₂)—, optionally substitutedcycloalkyl, optionally substituted alkyl, or optionally substitutedaryl; wherein L₂ is —C≡C—; and wherein B₂ is a covalent bond;

[0190] c) A₃—L₃—B₃—, wherein A₃ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₃ is a covalent bond; and wherein B₃ is —CH₂NH—;

[0191] d) A₄—L₄—B₄—, wherein A₄ is an optionally substituted aryl;wherein L₄ is —NHCH₂—; and wherein B₄ is a thienyl group;

[0192] e) A₅—L₅—B₅—, wherein A₅ is an optionally substituted heteroarylor optionally substituted heterocyclyl; wherein L₅ is a covalent bond;and wherein B₅ is —SCH₂—;

[0193] f) morpholinyl-CH₂—

[0194] g) optionally substituted aryl;

[0195] h) A₆—L₆—B₆—, wherein A₆ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₆ is a covalent bond; and wherein B₆ is —NHCH₂—;

[0196] i) A₇—L₇—B₇—, wherein A₇ is an optionally substituted heteroarylor optionally substituted heterocyclyl; wherein L₇ is a covalent bond;and wherein B₇ is —CH₂—;

[0197] j) aptionally substituted heteroaryl or optionally substitutedheterocyclyl;

[0198] k) A₈L₈—B₈—, wherein A₈ is optionally substituted phenyl; whereinL₈ is a covalent bond; and wherein B₈ is —O—;

[0199] l) A₉—L₉—B₉—, wherein A₉ is an optionally substituted aryl;wherein L₉ is a covalent bond; and wherein B₉ is a furan group;

[0200] m) A₁₀—L₁₀—B₁₀—, wherein A₁₀ is an optionally substitutedheteroaryl or optionally substituted heterocyclyl; wherein L₁₀ is—CH(CH₂CH₃)—; and wherein B₁₀ is —NHCH₂—;

[0201] n) A₁₁—L₁₁—B₁₁—, wherein A₁₁ is an optionally substitutedheteroaryl or optionally substituted heterocyclyl; wherein L₁₁ is acovalent bond; and wherein B₁₁ is —OCH₂—;

[0202] o) A₁₂—L₁₂—B₁₂—, wherein A₁₂ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁₂ is —NHC(O)—; and wherein B₁₂ is —N(optionallysubstituted aryl)CH₂—;

[0203] p) A₁₃—L₁₃—B₁₃—, wherein A₁₂ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁₃ is a covalent bond; and wherein B₁₃ is—NHC(O)—;

[0204] q) A₁₄—L₁₄—B₁₄—, wherein A₁₄ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁₄ is —NHC(O)(optionally substituted heteroaryl);and wherein B₁₄ is —S—S—;

[0205] r) F₃CC(O)NH—;

[0206] s) A₁₅—L₁₅—B₁₅—, wherein A₁₅ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁₅ is —(CH₂)₀₋₁NH(optionally substitutedheteroaryl)—; and wherein B₁₅ is —NHCH₂—;

[0207] t) A₁₆—L₁₆—B₁₆—, wherein A₁₆ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁₆ is a covalent bond; and wherein B₁₆ is—N(optionally substituted alkyl)CH₂—; and

[0208] u) A₁₆—L₁₆—B₁₆—, wherein A₁₆ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁₆ is a covalent bond; and wherein B₁₆ is—(optionally substituted aryl-CH₂)₂—N—.

[0209] In another preferred embodiment of the compounds according toparagraph [0093], Cy²—X¹— is collectively selected from the groupconsisting of

[0210] a) D₁—E₁—F₁—, wherein D₁ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₁ is —CH₂— or a covalent bond; and wherein B₁ isa covalent bond;

[0211] b) D₂—E₂—F₂—, wherein D₂ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₂ is —NH(CH₂)₀₋₂—; and wherein F₂ is a covalentbond;

[0212] c) D₃—E₃—F₃—, wherein D₃ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₃ is —(CH₂)₀₋₂NH—; and wherein F₃ is a covalentbond;

[0213] d) D₄—E₄—F₄—, wherein D₄ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₄ is —S(CH₂)₀₋₂—; and wherein F₄ is a covalentbond;

[0214] e) D₅—E₅—F₅—, wherein D₅ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₅ is —(CH₂)₀₋₂S—; and wherein F₅ is a covalentbond; and

[0215] f) D₆—E₆—F6—, wherein D₆ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₆ is —NH(CH₂)₀₋₂NH—; and wherein F₆ is a covalentbond.

[0216] In a preferred embodiment, the HDAC inhibitors of the inventioncomprise compounds of paragraph [0057] having formula (3b):

[0217] and pharmaceutically acceptable salts thereof, wherein Y and Zare independently N or CH and W is selected from the group consistingof:

and

[0218] In a preferred embodiment of the compounds according to paragraph[0096], the compounds comprise those wherein Y, Z and W are as definedbelow: Cpd W Y Z 164

CH CH 165

CH CH 166

CH CH 167

CH N 168

CH N 169

CH CH 170

CH CH 171

N CH 172

CH CH 174

CH N 175

CH N 176

CH N 177

CH CH 178

N CH 179

CH CH 180

CH CH 181

CH CH 182

CH CH and 183

CH CH

[0219] In another preferred embodiment of the compounds according toparagraph [0096], the compounds comprise those wherein Y, Z and W are asdefined below: Cpd W Y Z 187

CH CH 188

CH CH 189

CH CH 190

CH CH 193

CH CH 194

CH CH 195

CH CH 196

CH CH 320

CH CH 321

CH CH 322

CH CH 323

CH CH 325

CH CH 326

CH CH 327

CH CH 328

CH CH 329

CH CH 330

CH CH 331

CH CH 332

CH CH 333

CH CH 334

CH CH 335

CH CH 336

CH CH 337

CH CH 338

CH CH 339

CH CH 340

CH CH 341

CH CH 342

CH CH 343

CH CH 344

CH CH 345

CH CH 346

CH CH 347

CH CH 348

CH CH 349

CH CH 350

CH CH 351

CH CH 352

CH CH 353

CH CH 354

CH CH 355

CH CH 356

CH CH 357

CH CH 358

CH CH 359

CH CH 360

CH CH 361

CH CH 362

CH CH 363

CH CH 364

CH CH 365

CH CH 366

CH CH 367

CH CH 368

CH CH 369

CH CH 370

CH CH 371

CH CH 372

CH CH 373

CH CH 374

CH CH 375

CH CH 377

CH CH 378

CH CH 379

CH CH 380

CH CH 381

CH CH 382

CH CH 383

CH CH 384

CH CH 385

CH CH 386

CH CH 387

CH CH 388

CH CH 389

CH CH 390

CH CH 391

CH CH 392

CH CH 393

CH CH 394

CH CH 395

CH CH 396

CH CH 397

CH CH 398

CH N 399

CH CH 400

CH CH 401

CH CH 402

CH CH 403

CH CH 404

CH CH 405

CH CH 406

CH CH 407

CH CH 408

CH CH 409

CH CH 410

CH CH 411

CH CH 412

CH CH 413

CH CH 414

CH CH 415

CH CH 416

CH CH 417

CH CH 418

CH CH 419

CH CH 420

CH CH 421

CH CH 422

CH CH 423

CH CH 424b

CH CH 425

CH CH 426

CH CH 427

CH CH 428

CH CH 429

CH CH 430

CH CH 431

CH CH 432

CH CH 433

CH CH 434

CH CH 435

CH CH 436

CH CH 437

CH CH 438

CH CH 439

CH CH 440

CH CH 441

CH CH 442

CH CH 443

CH CH 444

CH CH 445

CH N 446

CH N 447

CH CH 448

CH CH 449

CH CH 450

CH CH 451

CH CH 452

CH CH 453

454

455

CH CH 456

CH CH 457

458

CH CH 459

CH CH 460

CH N 461

CH CH 462

CH CH 463

N CH 464

N CH 465

CH CH 466

CH CH 467

CH CH 468

CH CH

[0220] In yet another a preferred embodiment, the novel histonedeacetylase inhibitors of the on are selected from the group consistingof the following and their pharmaceutically able salts:

[0221] In another preferred embodiment, the compounds are selected fromthose listed in Tables 2a-b, 3a-d, 4a-c, and 5a-5f.

Synthesis

[0222] Compounds of formula (1), wherein Y¹ is —N(R¹)(R²), preferablymay be prepared according to the synthetic route depicted in Scheme 1.Thus, trichlorotriazine I reacts with amine II in the presence ofdiisopropylethylamine to produce dichloroaminotriazine III. The amineR¹R²NH is added to dichloroaminotriazine III to producediaminochlorotriazine V. Treatment of V with ammonia or R³R⁴NH intetrahydrofuran (THF) or 1,4 dioxane affords triaminotriazine VI.

[0223] Alternatively, dichloroaminotriazine III may be reacted withammonia gas in 1,4 dioxane to produce diaminochlorotriazine IV.Treatment of IV with R¹R²NH in THF or 1,4 dioxane in a sealed flask thenaffords triaminotriazine VI.

[0224] Hydrolysis of the ester moiety in VI is effected by treatmentwith a hydroxide base, such as lithium hydroxide, to afford thecorresponding acid VII. Treatment of the acid VlI with1,2-phenylenediamine in the presence of BOP reagent, triethylamine, anddimethylformamide (DMF) yields the anilinyl amide VII.

[0225] Compounds of formula (1), wherein Y¹ is —CH₂—C(O)—N(R¹)(R²),preferably may be prepared as outlined in Scheme 2. Thus, piperazine IXis treated with acetyl chloride and triethylamine to produce amide X.Reaction of X with dichloromorpholyltriazine and lithiumhexamethyidisiloxane affords compound XI. The chloride of XI isconverted to the anilinyl amide of XII as described above with respectto Scheme 1: treatment with the amine and diisopropylethylamine;followed by lithium hydroxide; followed by BOP reagent,phenylenediamine, triethylamine, and DMF.

[0226] Compounds of formula (2), wherein Ar² is pyridylene and X¹comprises —N(R⁷)—, compounds of formula (3), wherein Ar³ is pyridyleneand X² comprises —N(R⁹)—, and compounds of formula (4), wherein Ar⁴ ispyridylene and X³ comprises —N(R¹¹)—, preferably may be preparedaccording to the procedures illustrated in Scheme 3. Dibromopyridine XIIor XIV is treated with amine RNH₂ to produce aminobromopyridine XV orXVI, respectively. Treatment of XV or XVI with diacetoxypalladium,diphenylphosphinoferrocene, DMF, diisopropylethylamine, andphenylenediamine under carbon monoxide yields anilinyl amide XVII orXVIII, respectively.

[0227] Treatment of XV or XVI with tert-butylacrylate,diisopropylethylamine, dibenzylacetone palladium, andtri-o-tolylphosphine (POT) in DMF under nitrogen affords compounds XIXand XX, respectively. The ester moiety of XIX or XX is hydrolyzed toproduce the corresponding acid moiety in XXI or XXII, respectively, byreaction with trifluoroacetic acid in dichloromethane. Treatment of theacid XXI or XXII with phenylenediamine, BOP, and triethylamine affordsthe anilinyl amide XXIII or XXIV, respectively.

[0228] Compounds of formula (2), wherein X¹ comprises —O—C(O)—NH—,preferably may be prepared according to the synthetic route depicted inScheme 4. Thus, carbinol XXV is added to bromobenzylamine XXVI withcarbonyldiimidazole (CDI), triethylamine, and1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) in DMF to produce compoundXXVII. The remaining synthetic steps in the production of anilinyl amideXXVIII are as described above for Scheme 3.

[0229] Compounds of formula (2), wherein X¹ comprises —N(R⁷)—,preferably may be prepared as outlined in Scheme 5. Amine XXIX isreacted with p-bromobenzylbromide in the presence of potassium carbonatein DMF to produce bromobenzylamine XXX. Treatment of XXX withnitroacrylanilide, dibenzylacetone palladium, POT, anddiisopropylethylamine in DMF affords nitroanilide XXXI. NitroanilideXXXI is converted to the corresponding anilinyl amide XXXII by treatmentwith stannous chloride in methanol and water.

[0230] Treatment of amine XXXI in formic acid with paraformaldehydeprovides methylamine XXXIII. The nitroanilide moiety in XXXIII is thenconverted to the corresponding anilinyl amide moiety in XXXIV bytreatment with stannous chloride in methanol and water.

[0231] Alternatively, compounds of formula (2), wherein X¹ comprises—N(R⁷)—, may be prepared according to the synthetic route depicted inScheme 6. Carboxylic acid XXXV in methanol is treated with hydrochloricacid to produce ester XXXVI. Conversion of the primary amine moiety inXXXVI to the secondary amine moiety in XXXVI is effected by treatmentwith a catalyst such as triethylamine, methoxybenzylchloride, sodiumiodide, and potassium carbonate in DMF at 60° C. Ester XXXVI isconverted to anilinyl amide XXXVII by treatment with sodium hydroxide,THF, and methanol, followed by BOP, triethylamine, and phenylenediaminein DMF, as described above for Scheme 3.

[0232] Compounds of formula (2), wherein X¹ comprises

[0233] or —C(O)—NH—, preferably may be prepared according to theprocedures illustrated in Scheme 7. Addition of amine 68 to haloarylcompound XXXVIII or XXXIX and potassium carbonate in DMF providesarylamine XL or XLI, respectively. Anilinyl amide XLII or XLIII is thenprepared using procedures analogous to those set forth in Schemes 3-6above.

[0234] Compounds such as XLVII and XLIX preferably may be prepared asoutlined in Scheme 8. Dibromopyridine is combined with diaminoethane toproduce amine XLIV. Treatment of amine XLIV with isatoic anhydride LV inmethanol and water, followed by refluxing in formic acid affordscompound XLVI. Treatment of amine XLIV with the reaction products ofbenzylaminodiacetic acid and acetic anhydride provides compound XLVIII.Bromopyridylamines XLVI and XLVIII are then converted to thecorresponding diene anilinylamides XLVII and XLIX, respectively, byprocedures analogous to those set forth in Schemes 3-7 above.

[0235] Compounds such as LIV preferably may be prepared according to thesynthetic route depicted in Scheme 9. Trichlorotriazine is treated withaminoindan and diisopropylethylamine to produce dichloroaminotriazine L.Treatment with bromobenzylamine and diisopropylethylamine affordsdiaminochlorotriazine LI. Addition of ammonia gas and dioxane providestriaminotriazine LII. Treatment with protected acrylanilide,triethylamine, POT, and dibenzylacetone palladium then yields dieneanilinylamide LII, which is deprotected with trifluoroacetic acid toprovide the final product LIV.

[0236] Compounds of formula (2), wherein Ar² is quinolylene and X¹comprises —N(R⁷)—, compounds of formula (3), wherein Ar³ is quinolyleneand X² comprises —N(R⁹)—, and compounds of formula (4), wherein Ar⁴ isquinolylene and X³ comprises —N(R¹¹)—, preferably may be preparedaccording to the procedures illustrated in Scheme 10. DihydroxyquinolineLV with dimethylaminopyridine (DMAP) in pyridine is treated withtrifluoromethanesulfonic anhydride to providebis(trifluoromethanesulfonyloxy)-quinoline LVI. Treatment of LVI withp-methoxybenzylamine affords aminoquinoline LVII. Anilinyl amides LVIIIand LIX are then prepared using procedures analogous to those describedfor Schemes 1-9 above.

[0237] Compounds of formula (3), wherein X² comprises a sulfur atom, andcompounds of formula (4), wherein X³ comprises a sulfur atom, preferablymay be prepared as outlined in Scheme 11. Bromide LX is converted todiaryl ester LXI using procedures analogous to those described forScheme 6 above. Synthetic methods similar to those set forth in Scheme 1above are then used to convert ester LXI to the corresponding acid LXIV.Alternatively, ester LXI may be treated with chloroethylmorphonline,sodium iodide, potassium carbonate, triethylamine, andtetrabutylammonium iodide (TBAI) in DMF to produce ester LXIII, which isthen converted to acid LXIV as in Scheme 1. Conversion of the acid LXIVto the anilinyl amide LXV is effected by procedures analogous to thoseset forth in Scheme 1 above.

[0238] Alternatively, compounds of formula (3), wherein X² comprises asulfur atom, and compounds of formula (4), wherein X³ comprises a sulfuratom, may be prepared according to the procedures illustrated in Scheme12. Sulfanyl anilinylamide LXVIII is prepared using procedures analogousto those set forth in Schemes 3 and 5 above.

[0239] Compounds of formula (3), wherein X² comprises —N(R⁹)—, andcompounds of formula (4), wherein X³ comprises —N(R¹¹)—, preferably maybe prepared according to the synthetic route depicted in Scheme 13.Amino anilinyl amide LXXI is prepared according to synthetic stepssimilar to those described for Schemes 1 and 6 above.

[0240] Compounds of formula (3), wherein X² comprises a sulfur atom, andcompounds of formula (4), wherein X³ comprises a sulfur atom, preferablymay be prepared as outlined in Scheme 14. Phenylenediamine is reactedwith di-tert-butyldicarbonate, followed by iodobenzoic acid,dimethylaminopropylethylcarbodiimide, hydroxybenzotriazole, andtriethylamine to provide protected anilinyl amide LXXII. The iodidemoiety of LXXII is converted to the methyl ester moiety of LXXIII usingprocedures analogous to those set forth for Scheme 3 above. The methylester moiety of LXXIII is converted to the hydroxyl moiety of LXXIV bytreatment with a reducing agent such as diisobutylaluminum hydride(DIBAL-H). Addition of the heterocyclylsulfhydryl compound Het-SH withtriphenylphosphine and diethylazodicarboxylate converts the hydroxylmoiety of LXXIV to the sulfanyl moiety of LXXV. LXXV is deprotected withtrifluoroacetic acid to afford the sulfanyl anilinyl amide LXXVI.

[0241] Compounds of formula (3), wherein X² is a chemical bond,preferably may be prepared according to the synthetic route depicted inScheme 15. Thus, chloroarylanilinylamide LXXVII is treated with arylboronic acid, benzene, ethanol, aqueous sodium carbonate, andtriphenylphosphine palladium to afford the diarylanilinylamide LXXVIII.

[0242] Compounds such as LXXXI preferably may be prepared according tothe procedues illustrated in Scheme 16. Thus, benzene-1,2-carbaldehydeLXXIX in acetic acid is treated with p-aminomethylbenzoic acid toproduce the benzoic acid LXXX. The acid LXXX is converted to thecorresponding anilinylamide LXXXI by treatment withhydroxybenzotriazole, ethylenedichloride, and phenylenediamine.

[0243] Compounds such as LXXXVI and LXXXIX preferably may be preparedaccording to the procedures illustrated in Scheme 18. Phthalic anhydrideLXXXV and p-aminomethylbenzoic acid are combined in acetic acid toproduce an intermediate carboxylic acid, which is converted to theanilinylamide LXXXVI using procedures analogous to those set forth inSchemes 15 and 16 above.

[0244] The addition of 4-(2-aminoethyl)phenol to phthalic anhydrideLXXXV in acetic acid affords the hydroxyl compound LXXXVII. The hydroxylgroup of LXXXVII is converted to the triflate group of LXXXVIII bytreatment with sodium hydride, THF, DMF, and phenylaminoditriflate.Treatment of LXXXVIII according to procedures analogous to thosedescribed for Scheme 3 above affords the anilinylamide LXXXIX.

[0245] Compounds such as XCI-XCVI preferably may be prepared accordingto the synthetic route depicted in Scheme 19. Treatment of isatoicanhydride XC with p-aminomethylbenzoic acid in water and triethylamine,followed by formic acid affords an intermediate carboxylic acid, whichis converted to anilinylamide XCI using procedures analogous to thosedescribed for Scheme 16 above.

[0246] Alternatively, treatment of isatoic acid XC withp-aminomethylbenzoic acid in water and triethylamine, follwed byhydrochloric acid and sodium nitrite affords an intermediate carboxylicacid, which is converted to anilinylamide XCII using proceduresanalogous to those described for Scheme 16 above.

[0247] Alternatively, treatment of isatoic acid XC withp-aminomethylbenzoic acid in water and triethylamine affords benzoicacid XCIII. Treatment of XCIII with sodium hydroxide, dioxane,methylchloroformate, and methanol affords an intermediatequinazolinedione carboxylic acid, the acid moiety of which is thenconverted to the anilinylamide moiety of XCIV using procedures analogousto those described for Scheme 16 above. Alternatively, the intermediatequanzolinedione carboxylic acid in DMF is treated with potassiumcarbonate and methyl iodide to produce an intermediate benzoic acidmethyl ester, which is converted to an intermediate benzoic acid bytreatment with sodium hydroxide, methanol, and water. The benzoic acidis then converted to the corresponding anilinylamide XCV usingprocedures analogous to those described for Scheme 16 above.

[0248] Alternatively, treatment of XCIII with acetic anhydride followedby acetic acid produces an intermediate carboxylic acid, which isconverted to anilinylamide XCVI using procedures analogous to thosedescribed for Scheme 16 above.

[0249] Compounds such as C preferably may be prepared as outlined inScheme 20. Alkylamine XCVII is treated with thiocarbonyl diimidazole indichloromethane, follwed by ammonium hydroxide to afford thioureaXCVIII. Treatment of thiourea XCVIII with methylmethoxyacrylate indioxane and N-bromosuccinimide produces thiazole ester IC. The ester ICis converted to the corresponding anilinylamine C using proceduresanalogous to those set forth in Scheme 1 above.

[0250] Compounds of formula (3), wherein X² is a chemical bond and Cy³has an amino substituent preferably may be prepared according to thesynthetic route depicted in Scheme 21. Thus, protectediodoarylanilinylamide CI is treated according to procedures analogous tothose described for Scheme 15 above afford the diarylanilinylamide CII.The aldehyde moiety in CII is converted to the corresponding secondaryamine moiety by treatment with the primary amine and sodiumtriacetoxyborohydride followed by glacial acetic acid. The resultantcompound is deprotected to yield CIII using procedures analogous tothose set forth in Scheme 3 above.

[0251] Compounds of formula (3), wherein X² comprises an alkynylenemoiety, and compounds of formula (4), wherein X³ comprises an alkynylenemoiety, preferably may be prepared as outlined in Scheme 22. Treatmentof protected iodoarylanilinylamide CI with triphenylphosphine palladiumchloride, cuprous iodide, and 1-ethynylcyclohexylamine affords thealkynylarylanilinylamide CIV. The primary amine moiety in CIV isconverted to the corresponding secondary amine and the aniline moiety isdeprotected to afford CV using procedures analogous to those describedfor Scheme 21 above.

[0252] Compounds such as CVIII preferably may be prepared according tothe synthetic route depicted in Scheme 24. Dichloroaminotriazine CVI istreated with methyl-4aminobenzoate in the presence ofdiisopropylethylamine to produce diaminotriazine CVII. Addition ofammonia gas and dioxane, followed by a saponification and a peptidecoupling using the same procedures analogous to those described forScheme 1 above.

[0253] Compounds such as CX preferably may be prepared according to thesynthetic route depicted in Scheme 30. The Grignard reaction oftrichloroaminotriazine with various alkyl magnesium bromide, followed bya treatment with methyl-4-aminobenzoate in the presence ofdiisopropylethylamine yields alkylaminotriazine CIX. Synthetic methodssimilar to those set forth in Scheme 1 above are then used to convertester CIX to the corresponding anilinyl amide CX.

[0254] Amination of dichlorotriazine proceeded using the usual conditiondescribed in Scheme 1 to afford CXI. Stille coupling using vinylstannane provides CXII. Treatment with protected iodoanilide,triethylamine, POT and dibenzylacetone palladium then yieldsanilinylamide, which is deprotected with trifluoroacetic acid to providethe alkene CXIII. Hydrogenation of the alkene affords the final compoundCXIV.

[0255] Compounds such as CXVIII preferably may be prepared according tothe synthetic route depicted in Scheme 33. Treatment ofmethoxyaminobenzothiazole with tribromide boron affords thecorresponding acid CXV. Mitsunobu reaction using hydroxyethyl morpholinein the presence of diethylazodicarboxylate and triphenylphosphine yieldsthe amine CXVI. Reductive amination with methyl-4-formylbenzoate usingphenylsilane and tin catalyst yields to the ester CXVII. Saponificationfollowed by the usual peptide coupling analogous to those describe forScheme 1 above provides the desired anilide CXVIII.

[0256] Treatment 4-methylcyanobenzoic acid with hydrogen sulfide affordsCXIX, which is subjected to cyclization in the presence of1,3-dichloroacetone to yield CXX. Treatment with morpholine followed bya peptide coupling using the standard condition produces CXXI.

[0257] Compounds such as CXXIII and CXXVII preferably may be preparedaccording to the synthetic scheme 49. Consecutive treatment of acetylacetone with methyl bromomethylbenzoate in the presence of NaOMe andphenyl hydrazine followed by saponification, afforded the intermediateacid CXXII. This material was coupled with 1,2-diaminobenzene in astandard fashion to afford CXXIII.

[0258] Consecutive treatment of acetyl acetone with methylbromomethylbenzoate in the presence of NaOMe and a 1:1 mixture AcOH—HCl(conc.) afforded the intermediate acid CXXIV. This keto-acid reactingwith sulfur and malonodinitrile in the presence of a base, produced thethiophene CXXV, which was converted into the desired CXXVII usingstandard procedures.

[0259] Compounds such as CXXX preferably may be prepared according tothe synthetic scheme 50. Treatment of 4-cyanomethylbenzoic acid withhydroxylamine produced the amidoxime CXXVIII, which upon treatment withacetic anhydride was converted into the oxadiazole CXXIX. The lafter wascoupled with 1,2-diaminobenzene in a standard fashion to afford CXXX.

[0260] Compounds such as CXXXIII preferably may be prepared according tothe synthetic route depicted in Scheme 57. Treatment of 4-formylbenzoicacid with thionyl chloride afford the acyl chloride which is coupledwith protected anilide to produce CXXXI. Reductive amination withdimethoxyaniline using phenylsilane and tin catalyst yields to theprotected anilide CXXXII. Treatment with isocyanate followed bydeprotection with trifluoroacetic acid provides the ureidoanilideCXXXIII.

Pharmaceutical Compositions

[0261] In a second aspect, the invention provides pharmaceuticalcompositions comprising an inhibitor of histone deacetylase according tothe invention and a pharmaceutically acceptable carrier, excipient, ordiluent. Compounds of the invention may be formulated by any method wellknown in the art and may be prepared for administration by any route,including, without limitation, parenteral, oral, sublingual,transdermal, topical, intranasal, intratracheal, or intrarectal. Incertain preferred embodiments, compounds of the invention areadministered intravenously in a hospital setting. In certain otherpreferred embodiments, administration may preferably be by the oralroute.

[0262] The characteristics of the carrier will depend on the route ofadministration. As used herein, the term “pharmaceutically acceptable”means a non-toxic material that is compatible with a biological systemsuch as a cell, cell culture, tissue, or organism, and that does notinterfere with the effectiveness of the biological activity of theactive ingredient(s). Thus, compositions according to the invention maycontain, in addition to the inhibitor, diluents, fillers, salts,buffers, stabilizers, solubilizers, and other materials well known inthe art. The preparation of pharmaceutically acceptable formulations isdescribed in, e.g., Remington's Pharmaceutical Sciences, 18th Edition,ed. A. Gennaro, Mack Publishing Co., Easton, Pa., 1990.

[0263] As used herein, the term pharmaceutically acceptable salts refersto salts that retain the desired biological activity of theabove-identified compounds and exhibit minimal or no undesiredtoxicological effects. Examples of such salts include, but are notlimited to acid addition salts formed with inorganic acids (for example,hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid,nitric acid, and the like), and salts formed with organic acids such asacetic acid, oxalic acid, tartaric acid, succinic acid, malic acid,ascorbic acid, benzoic acid, tannic acid, pamoic acid, alginic acid,polyglutamic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid,and polygalacturonic acid. The compounds can also be administered aspharmaceutically acceptable quaternary salts known by those skilled inthe art, which specifically include the quaternary ammonium salt of theformula —NR+Z—, wherein R is hydrogen, alkyl, or benzyl, and Z is acounterion, including chloride, bromide, iodide, —O-alkyl,toluenesulfonate, methylsulfonate, sulfonate, phosphate, or carboxylate(such as benzoate, succinate, acetate, glycolate, maleate, malate,citrate, tartrate, ascorbate, benzoate, cinnamoate, mandeloate,benzyloate, and diphenylacetate).

[0264] The active compound is included in the pharmaceuticallyacceptable carrier or diluent in an amount sufficient to deliver to apatient a therapeutically effective amount without causing serious toxiceffects in the patient treated. A preferred dose of the active compoundfor all of the above-mentioned conditions is in the range from about0.01 to 300 mg/kg, preferably 0.1 to 100 mg/kg per day, more generally0.5 to about 25 mg per kilogram body weight of the recipient per day. Atypical topical dosage will range from 0.01-3% wt/wt in a suitablecarrier. The effective dosage range of the pharmaceutically acceptablederivatives can be calculated based on the weight of the parent compoundto be delivered. If the derivative exhibits activity in itself, theeffective dosage can be estimated as above using the weight of thederivative, or by other means known to those skilled in the art.

Inhibition of Histone Deacetylase

[0265] In a third aspect, the invention provides a method of inhibitinghistone deacetylase in a cell, comprising contacting a cell in whichinhibition of histone deacetylase is desired with an inhibitor ofhistone deacetylase according to the invention. Because compounds of theinvention inhibit histone deacetylase, they are useful research toolsfor in vitro study of the role of histone deacetylase in biologicalprocesses. In addition, the compounds of the invention selectivelyinhibit certain isoforms of HDAC.

[0266] Measurement of the enzymatic activity of a histone deacetylasecan be achieved using known methodologies. For example, Yoshida et al.,J. Biol. Chem., 265: 17174-17179 (1990), describes the assessment ofhistone deacetylase enzymatic activity by the detection of acetylatedhistones in trichostatin A treated cells. Taunton et al., Science, 272:408-411 (1996), similarly describes methods to measure histonedeacetylase enzymatic activity using endogenous and recombinant HDAC-1.

[0267] In some preferred embodiments, the histone deacetylase inhibitoririteracts with and reduces the activity of all histone deacetylases inthe cell. In some other preferred embodiments according to this aspectof the invention, the histone deacetylase inhibitor interacts with andreduces the activity of fewer than all histone deacetylases in the cell.In certain preferred embodiments, the inhibitor interacts with andreduces the activity of one histone deacetylase (e.g., HDAC-1), but doesnot interact with or reduce the activities of other histone deacetylases(e.g., HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC-7, and HDAC-8). Asdiscussed below, certain particularly preferred histone deacetylaseinhibitors are those that interact with, and reduce the enzymaticactivity of, a histone deacetylase that is involved in tumorigenesis.Certain other preferred histone deacetylase inhibitors interact with andreduce the enzymatic activity of a fungal histone deacetylase.

[0268] Preferably, the method according to the third aspect of theinvention causes an inhibition of cell proliferation of the contactedcells. The phrase “inhibiting cell proliferation” is used to denote anability of an inhibitor of histone deacetylase to retard the growth ofcells contacted with the inhibitor as compared to cells not contacted.An assessment of cell proliferation can be made by counting contactedand non-contacted cells using a Coulter Cell Counter (Coulter, Miami,Fla.) or a hemacytometer. Where the cells are in a solid growth (e.g., asolid tumor or organ), such an assessment of cell proliferation can bemade by measuring the growth with calipers and comparing the size of thegrowth of contacted cells with non-contacted cells.

[0269] Preferably, growth of cells contacted with the inhibitor isretarded by at least 50% as compared to growth of non-contacted cells.More preferably, cell proliferation is inhibited by 100% (i.e., thecontacted cells do not increase in number). Most preferably, the phrase“inhibiting cell proliferation” includes a reduction in the number orsize of contacted cells, as compared to non-contacted cells. Thus, aninhibitor of histone deacetylase according to the invention thatinhibits cell proliferation in a contacted cell may induce the contactedcell to undergo growth retardation, to undergo growth arrest, to undergoprogrammed cell death (i.e., to apoptose), or to undergo necrotic celldeath.

[0270] The cell proliferation inhibiting ability of the histonedeacetylase inhibitors according to the invention allows thesynchronization of a population of asynchronously growing cells. Forexample, the histone deacetylase inhibitors of the invention may be usedto arrest a population of non-neoplastic cells grown in vitro in the G1or G2 phase of the cell cycle. Such synchronization allows, for example,the identification of gene and/or gene products expressed during the G1or G2 phase of the cell cycle. Such synchronization of cultured cellsmay also be useful for testing the efficacy of a new transfectionprotocol, where transfection efficiency varies and is dependent upon theparticular cell cycle phase of the cell to be transfected. Use of thehistone deacetylase inhibitors of the invention allows thesynchronization of a population of cells, thereby aiding detection ofenhanced transfection efficiency.

[0271] In some preferred embodiments, the contacted cell is a neoplasticcell. The term “neoplastic cell” is used to denote a cell that showsaberrant cell growth. Preferably, the aberrant cell growth of aneoplastic cell is increased cell growth. A neoplastic cell may be ahyperplastic cell, a cell that shows a lack of contact inhibition ofgrowth in vitro, a benign tumor cell that is incapable of metastasis invivo, or a cancer cell that is capable of metastasis in vivo and thatmay recur after attempted removal. The term “tumorigenesis” is used todenote the induction of cell proliferation that leads to the developmentof a neoplastic growth. In some embodiments, the histone deacetylaseinhibitor induces cell differentiation in the contacted cell. Thus, aneoplastic cell, when contacted with an inhibitor of histone deacetylasemay be induced to differentiate, resulting in the production of anon-neoplastic daughter cell that is phylogenetically more advanced thanthe contacted cell.

[0272] In some preferred embodiments, the contacted cell is in ananimal. Thus, the invention provides a method for treating a cellproliferative disease or condition in an animal, comprisingadministering to an animal in need of such treatment a therapeuticallyeffective amount of a histone deacetylase inhibitor of the invention.Preferably, the animal is a mammal, more preferably a domesticatedmammal. Most preferably, the animal is a human.

[0273] The term “cell proliferative disease or condition” is meant torefer to any condition characterized by aberrant cell growth, preferablyabnormally increased cellular proliferation. Examples of such cellproliferative diseases or conditions include, but are not limited to,cancer, restenosis, and psoriasis. In particularly preferredembodiments, the invention provides a method for inhibiting neoplasticcell proliferation in an animal comprising administering to an animalhaving at least one neoplastic cell present in its body atherapeutically effective amount of a histone deacetylase inhibitor ofthe invention.

[0274] It is contemplated that some compounds of the invention haveinhibitory activity against a histone deacetylase from a protozoalsource. Thus, the invention also provides a method for treating orpreventing a protozoal disease or infection, comprising administering toan animal in need of such treatment a therapeutically effective amountof a histone deacetylase inhibitor of the invention. Preferably theanimal is a mammal, more preferably a human. Preferably, the histonedeacetylase inhibitor used according to this embodiment of the inventioninhibits a protozoal histone deacetylase to a greater extent than itinhibits mammalian histone deacetylases, particularly human histonedeacetylases.

[0275] The present invention further provides a method for treating afungal disease or infection comprising administering to an animal inneed of such treatment a therapeutically effective amount of a histonedeacetylase inhibitor of the invention. Preferably the animal is amammal, more preferably a human. Preferably, the histone deacetylaseinhibitor used according to this embodiment of the invention inhibits afungal histone deacetylase to a greater extent than it inhibitsmammalian histone deacetylases, particularly human histone deacetylases.

[0276] The term “therapeutically effective amount” is meant to denote adosage sufficient to cause inhibition of histone deacetylase activity inthe cells of the subject, or a dosage sufficient to inhibit cellproliferation or to induce cell differentiation in the subject.Administration may be by any route, including, without limitation,parenteral, oral, sublingual, transdermal, topical, intranasal,intratracheal, or intrarectal. In certain particularly preferredembodiments, compounds of the invention are administered intravenouslyin a hospital setting. In certain other preferred embodiments,administration may preferably be by the oral route.

[0277] When administered systemically, the histone deacetylase inhibitoris preferably administered at a sufficient dosage to attain a bloodlevel of the inhibitor from about 0.01 μM to about 100 μM, morepreferably from about 0.05 μM to about 50 μM, still more preferably fromabout 0.1 μM to about 25 μM, and still yet more preferably from about0.5 μM to about 25 μM. For localized administration, much lowerconcentrations than this may be effective, and much higherconcentrations may be tolerated. One of skill in the art will appreciatethat the dosage of histone deacetylase inhibitor necessary to produce atherapeutic effect may vary considerably depending on the tissue, organ,or the particular animal or patient to be treated.

[0278] In certain preferred embodiments of the third aspect of theinvention the method further comprises contacting the cell with anantisense oligonucleotide that inhibits the expression of a histonedeacetylase. The combined use of a nucleic acid level inhibitor (e.g.,antisense oligonucleotide) and a protein level inhibitor (i.e.,inhibitor of histone deacetylase enzyme activity) results in an improvedinhibitory effect, thereby reducing the amounts of the inhibitorsrequired to obtain a given inhibitory effect as compared to the amountsnecessary when either is used individually. The antisenseoligonucleotides according to this aspect of the invention arecomplementary to regions of RNA or double-stranded DNA that encodeHDAC-1, HDAC-2, HDAC-3, HDAC-4, HDAC-5, HDAC-6, HDAC7, and/or HDAC-8(see e.g., GenBank Accession Number U50079 for HDAC-1, GenBank AccessionNumber U31814 for HDAC-2, and GenBank Accession Number U75697 forHDAC-3).

[0279] For purposes of the invention, the term “oligonucleotide”includes polymers of two or more deoxyribonucleosides, ribonucleosides,or 2′-substituted ribonucleoside residues, or any combination thereof.Preferably, such oligonucleotides have from about 6 to about 100nucleoside residues, more preferably from about 8 to about 50 nucleosideresidues, and most preferably from about 12 to about 30 nucleosideresidues. The nucleoside residues may be coupled to each other by any ofthe numerous known internucleoside linkages. Such internucleosidelinkages include without limitation phosphorothioate,phosphorodithioate, alkylphosphonate, alkylphosphonothioate,phosphotriester, phosphoramidate, siloxane, carbonate,carboxymethylester, acetamidate, carbamate, thioether, bridgedphosphoramidate, bridged methylene phosphonate, bridged phosphorothioateand sulfone internucleoside linkages. In certain preferred embodiments,these internucleoside linkages may be phosphodiester, phosphotriester,phosphorothioate, or phosphoramidate linkages, or combinations thereof.The term oligonucleotide also encompasses such polymers havingchemically modified bases or sugars and/or having additionalsubstituents, including without limitation lipophilic groups,intercalating agents, diamines and adamantane.

[0280] For purposes of the invention the term “2′-substitutedribonucleoside” includes ribonucleosides in which the hydroxyl group atthe 2′ position of the pentose moiety is substituted to produce a2′-O-substituted ribonucleoside. Preferably, such substitution is with alower alkyl group containing 1-6 saturated or unsaturated carbon atoms,or with an aryl or allyl group having 2-6 carbon atoms, wherein suchalkyl, aryl or allyl group may be unsubstituted or may be substituted,e.g., with halo, hydroxy, trifluoromethyl, cyano, nitro, acyl, acyloxy,alkoxy, carboxyl, carbalkoxyl, or amino groups. The term “2′-substitutedribonucleoside” also includes ribonucleosides in which the 2′-hydroxylgroup is replaced with an amino group or with a halo group, preferablyfluoro.

[0281] Particularly preferred antisense oligonucleotides utilized inthis aspect of the invention include chimeric oligonucleotides andhybrid oligonucleotides.

[0282] For purposes of the invention, a “chimeric oligonucleotide”refers to an oligonucleotide having more than one type ofinternucleoside linkage. One preferred example of such a chimericoligonucleotide is a chimeric oligonucleotide comprising aphosphorothioate, phosphodiester or phosphorodithioate region,preferably comprising from about 2 to about 12 nucleotides, and analkylphosphonate or alkylphosphonothioate region (see e.g., Pederson etal. U.S. Pat. Nos. 5,635,377 and 5,366,878). Preferably, such chimericoligonucleotides contain at least three consecutive internucleosidelinkages selected from phosphodiester and phosphorothioate linkages, orcombinations thereof.

[0283] For purposes of the invention, a “hybrid oligonucleotide” refersto an oligonucleotide having more than one type of nucleoside. Onepreferred example of such a hybrid oligonucleotide comprises aribonucleotide or 2′-substituted ribonucleotide region, preferablycomprising from about 2 to about 12 2′-substituted nucleotides, and adeoxyribonucleotide region. Preferably, such a hybrid oligonucleotidecontains at least three consecutive deoxyribonucleosides and alsocontains ribonucleosides, 2′-substituted ribonucleosides, preferably2′-O-substituted ribonucleosides, or combinations thereof (see e.g.,Metelev and Agrawal, U.S. Pat. No. 5,652,355).

[0284] The exact nucleotide sequence and chemical structure of anantisense oligonucleotide utilized in the invention can be varied, solong as the oligonucleotide retains its ability to inhibit expression ofthe gene of interest. This is readily determined by testing whether theparticular antisense oligonucleotide is active. Useful assays for thispurpose include quantitating the mRNA encoding a product of the gene, aWestern blotting analysis assay for the product of the gene, an activityassay for an enzymatically active gene product, or a soft agar growthassay, or a reporter gene construct assay, or an in vivo tumor growthassay, all of which are described in detail in this specification or inRamchandani et al. (1997) Proc. Natl. Acad. Sci. USA 94: 684-689.

[0285] Antisense oligonucleotides utilized in the invention mayconveniently be synthesized on a suitable solid support using well knownchemical approaches, including H-phosphonate chemistry, phosphoramiditechemistry, or a combination of H-phosphonate chemistry andphosphoramidite chemistry (i.e., H-phosphonate chemistry for some cyclesand phosphoramidite chemistry for other cycles). Suitable solid supportsinclude any of the standard solid supports used for solid phaseoligonucleotide synthesis, such as controlled-pore glass (CPG) (see,e.g., Pon, R. T. (1993) Methods in Molec. Biol. 20: 465-496).

[0286] Particularly preferred oligonucleotides have nucleotide sequencesof from about 13 to about 35 nucleotides which include the nucleotidesequences shown in Table 1. Yet additional particularly preferredoligonucleotides have nucleotide sequences of from about 15 to about 26nucleotides of the nucleotide sequences shown in Table 1. TABLE 1Accession position within Oligo Target Number Nucleotide PositionSequence Gene HDAC1 AS1 Human HDAC1 U50079 1585-16045′-GAAACGTGAGGGACTCAGCA-3′ 3′-UTR HDAC1 AS2 Human HDAC1 U50079 1565-15845′-GGAAGCCAGAGCTGGAGAGG-3′ 3′-UTR HDAC1 MM Human HDAC1 U50079 1585-16045′-GTTAGGTGAGGCACTGAGGA-3′ 3′-UTR HDAC2 AS Human HDAC2 U31814 1643-16225′-GCTGAGCTGTTCTGATTTGG-3′ 3′-UTR HDAC2 MM Human HDAC2 U31814 1643-16225′-CGTGAGCACTTCTCATTTCC-3′ 3′-UTR HDAC3 AS Human HDAC3 AF0397031276-1295 5′-CGCTTTCCTTGTCATTGACA-3′ 3′-UTR HDAC3 MM Human HDAC3AF039703 1276-1295 5′-GCCTTTCCTACTCATTGTGT-3′ 3′-UTR HDAC4 AS1 HumanHDAC4 AB006626 514-33  5′-GCTGCCTGCCGTGCCCACCC-3′ 5′-UTR HDAC4 MM1 HumanHDAC4 AB006626 514-33  5′-CGTGCCTGCGCTGCCCACGG-3′ 5′-UTR HDAC4 AS2 HumanHDAC4 AB006626 7710-29   5′-TACAGTCCATGCAACCTCCA-3′ 3′-UTR HDAC4 MM4Human HDAC4 AB006626 7710-29   5′-ATCAGTCCAACCAACCTCGT-3′ 3′-UTR HDAC5AS Human HDAC5 AF039691 2663-2682 5′-CTTCGGTCTCACCTGCTTGG-3′ 3′-UTRHDAC6 AS Human HDAC6 AJ011972 3791-3810 5′-CAGGCTGGAATGAGCTACAG-3′3′-UTR HDAC6 MM Human HDAC6 AJ011972 3791-38105′-GACGCTGCAATCAGGTAGAC-3′ 3′-UTR HDAC7 AS Human HDAC7 AF2392432896-2915 5′-CTTCAGCCAGGATGCCCACA-3′ 3′-UTR HDAC8 AS1 Human HDAC8AF230097 51-70 5′-CTCCGGCTCCTCCATCTTCC-3′ 5′-UTR HDAC8 AS2 Human HDAC8AF230097 1328-1347 5′-AGCCAGCTGCCACTTGATGC-3′ 3′-UTR

[0287] The following examples are intended to further illustrate certainpreferred embodiments of the invention, and are not intended to limitthe scope of the invention.

EXAMPLES

[0288]

Example 14-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-benzamide(compound 8)

[0289] Step 1:Methyl-4-[(4,6-dichloro-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate(compound 3)

[0290] To a stirred solution at −78° C. of cyanuric chloride 1 (8.23 g,44.63 mmol) in anhydrous THF (100 mL) under nitrogen was added asuspension of methyl 4-(aminomethyl)benzoate.HCl 2 (10.00 g, 49.59mmol), in anhydrous THF (50 mL), followed by i-Pr₂NEt (19.00 mL, 109.10mmol). After 30 min, the reaction mixture was poured into a saturatedaqueous solution of NH₄Cl, and diluted with AcOEt. After separation, theorganic layer was successively washed with sat. NH₄Cl, H₂O and brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (AcOEt/CH₂Cl₂:5/95) to afford the title compound 3 (12.12 g, 38.70 mmol, 87% yield) asa pale yellow solid. ¹H NMR (300 MHz, CDCl₃) δ(ppm): AB system(δ_(A)=8.04, δ_(B)=7.38, J=8.5 Hz, 4H), 6.54 (bt, 1H), 4.76 (d, J=6.3Hz, 2H), 3.93 (s,3H).

[0291] Pathway A

[0292] Step 2:Methyl-4-[(4-amino-6-chloro-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate(compound 4)

[0293] In a 150 mL sealed flask, a solution of 3 (6.00 g, 19.16 mmol) inanhydrous 1,4-dioxane (60 mL) was stirred at room temperature, saturatedwith NH₃ gas for 5 min, and warmed to 70° C. for 6 h. The reactionmixture was allowed to cool to room temperature, the saturation stepwith NH₃ gas was repeated at room temperature for 5 min, and thereaction mixture was warmed to 70° C. again for 18 h. Then, the reactionmixture was allowed to cool to room temperature, poured into a saturatedaqueous solution of NH₄Cl, and diluted with AcOEt. After separation, theorganic layer was successively washed with sat. NH₄Cl, H₂O and brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (AcOEt/CH₂Cl₂:30/70) to afford the title compound 4 (5.16 g, 17.57 mmol, 91% yield) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ(ppm): AB system (δ_(A)=8.01,δ_(B)7.35, J=8.1 Hz, 4H), 5.79 (bs, 1H), 5.40-5.20 (m, 2H), 4.72-4.63(m, 2H), 3.91 (s, 3H).

[0294] Pathway B

[0295] Step 2: Methyl4-[(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate(compound 5)

[0296] To a stirred solution at room temperature of 3 (3.00 g, 9.58mmol) in anhydrous THF (50 mL) under nitrogen were added i-Pr₂NEt (8.34mL, 47.90 mmol) and 2-aminoindan.HCl (1.95 g, 11.50 mmol) or R¹R²NH (1.2equiv), respectively. After 18 h, the reaction mixture was poured into asaturated aqueous solution of NH₄Cl, and diluted with AcOEt. Afterseparation, the organic layer was successively washed with sat. NH₄Cl,H₂O and brine, dried over anhydrous MgSO₄, filtered and concentrated toafford the title compound 5 (4.06 g, 9.91 mmol, quantitative yield) as awhite powder. ¹H NMR (300 MHz, CDCl₃) δ(ppm): mixture of rotamers,8.06-7.94 (m, 2H), 7.43-7.28 (m, 2H), 7.24-7.12 (m, 4H), 6.41 and 6.05(2 bt, 1H), 5.68-5.44 (m, 1H), 4.92-4.54 (m, 3H), 3.92 (bs, 3H),3.41-3.12 (m, 2H), 2.90-2.70 (m, 2H).

[0297] Step 3:Methyl-4-[(4-amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-methyl]-benzoate(compound 6)

[0298] General Procedure for the Amination with NH₃ Gas

[0299] In a 150 mL sealed flask, a solution of 5 (3.90 g, 9.51 mmol) inanhydrous 1,4-dioxane (80 mL) was stirred at room temperature, saturatedwith NH₃ gas for 5 min, and warmed to 140° C. for 6 h. The reactionmixture was allowed to cool to room temperature, the saturation stepwith NH₃ gas was repeated for 5 min, and the reaction mixture was warmedto 140° C. again for 18 h. Then, the reaction mixture was allowed tocool to room temperature, poured into a saturated aqueous solution ofNH₄Cl, and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 3/97) to afford thetitle compound 6 (3.50 g, 8.96 mmol, 94% yield) as a pale yellow stickysolid. ¹H NMR (300 MHz, CDCl₃) δ(ppm): 7.99 (bd, J=8.2 Hz, 2H),7.41-7.33 (m, 2H), 7.24-7.13 (m,4H), 5.50-5.00 (m, 2H), 4.90-4.55 (m,5H), 3.92 (s, 3H), 3.40-3.10 (m, 2H), 2.90-2.70 (m, 2H), ¹³C NMR: (75MHz, CDCl₃) δ(ppm): 166.88, 167.35, 166.07, 144.77, 141.07, 129.82,128.93, 127.01, 126.61, 124.70, 52.06, 51.80, 44.25, 40.16. HRMS(calc.): 390.1804, (found): 390.1800.

[0300] Pathways A and B, Step 3, General Procedure with Primary and/orSecondary Amines

[0301] In a 50-75 mL sealed flask, a stirred solution of 4 (500 mg, 1.70mmol, 1 equiv), i-Pr₂NEt (1.48 mL, 8.51 mmol, 5 equiv) and R¹R²NH orR³R⁴NH (1.5-3 equiv) in anhydrous THF or 1,4-dioxane (20-30 mL) waswarmed to 120-140° C. for 15-24 h. Then, the reaction mixture wasallowed to cool to room temperature, poured into a saturated aqueoussolution of NH₄Cl, and diluted with AcOEt. After separation, the organiclayer was successively washed with sat. NH₄Cl, H₂O and brine, dried overanhydrous MgSO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel to afford the titlecompound.

[0302] Step 4:4-[(4-Amino-6-(2-indanyl-amino)-[1,3.5triazin-2-yl-aminoymethyl]-benzoicacid (compound 7)

[0303] To a stirred solution at room temperature of 6 (2.07 g, 5.30mmol) in THF (50 mL) was added a solution of LiOH.H₂O (334 mg, 7.96mmol) in water (25 mL). After 18 h, the reaction mixture was diluted inwater and acidified with 1 N HCl until pH 5-6 in order to get a whiteprecipitate. After 1 h, the suspension was filtered off and the cake wasabundantly washed with water, and dried to afford the title compound 7(1.73 g, 4.60 mmol, 87% yield) as a white solid. ¹H NMR (300 MHz,acetone-d₆) δ(ppm): 8.05 (bd, J=8.1 Hz, 2H), 7.56-7.42 (m, 2H),7.30-7.10 (m, 4H), 5.90-5.65 (m, 2H), 4.85-4.60 (m, 4H), 3.40-2.80 (m,4H). HRMS (calc.): 376.1648, (found): 376.1651.

[0304] Step 5:4-{[4-Amino-6-indanyl-amino)-[1,3,5]-triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-benzamide(compound 8)

[0305] To a stirred solution at room temperature of 7 (200 mg, 0.53mmol) in anhydrous DMF (5 mL) under nitrogen were added Et₃N (74 μl,0.53 mmol) and BOP reagent (282 mg, 0.64 mmol), respectively. After 40min, a solution of 1,2-phenylenediamine (64 mg, 0.58 mmol), Et₃N (222μl, 1.59 mmol) in anhydrous DMF (2 mL) was added dropwise. After 1.5 h,the reaction mixture was poured into a saturated aqueous solution ofNH₄Cl, and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 2/98→5/95) to affordthe title compound 8 (155 mg, 0.33 mmol, 63% yield) as a pale yellowfoam. ¹H NMR (300 MHz, acetone-d₆) δ(ppm): 9.04 (bs, 1H), 7.96 (bd,J=8.0 Hz, 2H), 7.50-7.40 (m, 2H), 7.30 (dd, J=8.0 Hz, 1.4 Hz, 1H),7.22-7.08 (m, 4H), 6.99 (ddd, J=8.0 Hz, 7.5 Hz, 1.5 Hz, 1H), 6.86 (dd,J=8.0 Hz, 1.4 Hz, 1H), 6.67 (dt, J=7.5 Hz, 1.4 Hz, 1H), 6.60-5.49 (m,4H), 4.80-4.50 (m, 4H), 3.30-3.08 (m, 2H), 2.96-2.74 (m, 2H).

EXAMPLES 2-28

[0306] Examples 2 to 28 describe the preparation of compounds 9 to 35using the same procedure as described for compound 8 of Example 1.Characterization data are presented in Tables 2a and 2b. TABLE 2aCharacterization of Compounds Prepared in Examples 2-28

Ex. Cpd Y X Name Characterization Schm 2 9

NH₂ 4-[(4-amino-6-morpholin- 4-yl-[1,3,5]-triazin-2-ylamino)-methyl]-N-(2- amino-phenyl)- benzamide ′H NMR (CDCl₃) δ (ppm):8.02 (s, 1H), 7.79 (d, J=8.0 # Hz, 2H), 7.34 (d, J=8.0 Hz, 2H), 7.31 (m,1H), 7.08 (dt, J=7.6 Hz, 1.5 Hz, 1H), 6.82 (t, J=6.7 Hz, 2H), 5.62 (t,J=5.9 Hz, 1H), 4.90 (bs, 2H), 4.61 (d, J=6.0 Hz, 2H), 3.75-3.62 (m,10H). 1A 3 10

NH₂ 4-{[4-amino-6-(1-indanyl- amino)-[1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ(ppm): 9.07 (bs, 1H), 8.05-7.95 (m, # 2H), 7.55-7.45 (m, 2H), 7.37-7.10(m, 5H), 7.04 (dt, J=7.6 Hz, 1.6 Hz, 1H), 6.90 (dd, J=8.0 Hz, 1.4 Hz,1H), 6.71 (dt, J=7.6 Hz, 1.4 Hz, 1H), 6.65-5.55 (m, 5H), 4.75-4.60 (m,3H), 3.05-2.75 (m, 2H), 2.60-2.45 (m, 1H)), 2.00-1.84 (m, 1H). HRMS(calc.): 466.2229, (found): 466.2225 1A 4 11

NH₂ N-(2-Amino-phenyl)-4-{[4- amino-6-(4-phenyl- piperazin-1-yl)-[1,3,5]triazin-2-ylamino]- methyl}-benzamide ¹H NMR (acetone-d₆) δ(ppm): mixture of rotamers, 9.05-9.00 (m, 1H), 7.98 (d, J=8.8 Hz, 2H),7.93 (s), 7.84 (d, J=8.0 Hz), 7.72 (d, J=8.2 # Hz), 7.58-7.40 (m, 3H),7.31-7.19 (m, 3H), 7.12-7.05 (m), 6.98 (d, J=8.1 Hz, 2H), 6.86 (d, J=8.2Hz, 1H), 6.80 (t, J=7.1 Hz, 1H), 6.67 (t, J=7.7 Hz, 1H), 6.57-6.50 (m,1H), 5.78-5.60 (m, 2H), 4.67-4.64 (m, 2H), 3.88-3.84 (m, 4H), 3.14 (s,4H), HRMS (calc.): 477.2389 [M⁺ − NH₄], (found): 477.2383 1A 5 12

NH₂ 4-{[4-amino-6-(2- pyridinyl-methyl-amino)- [1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ(ppm): 9.08 (bs, 1H), 8.51 (bs, 1H), 8.05-7.90 (m, # 2H), 7.80-7.60 (m,1H), 7.55-7.15 (m, 5H), 7.04 (dt, J=7.6 Hz, 1.6 Hz, 1H), 6.90 (dd, J=8.0Hz, 1.4 Hz, 1H), 6.71 (dt, J=7.6 Hz, 1.4 Hz, 1H), 6.85-6.55 (m, 1H),5.84 (bs, 2H), 4.75-4.60 (m, 4H). HRMS (calc.): 441.2025, (found):441.2029 1A 6 13

4-{[4,6-bis-(2-indanyl- amino)-[1,3,5]-triazin-2- ylamino]-methyl}-N-(2-amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ (ppm): 9.08 (bs, 1H),8.05-7.95 (m, 2H), 7.56-7.44 (m, 2H), 7.34 (bd, J=7.7 Hz, 1H), 7.27-7.10(m, 8H), 7.04 (td, J=7.6 Hz, 1.4 Hz, 1H), 6.90 (dd, J=8.0 Hz, 1.4 Hz,1H), 6.71 (dt, J=7.6 Hz, 1.4 Hz, 1H), 6.65-5.90 (m, 3H), 4.90-4.58 (m,6H), 3.40-2.80 (m, 4H). HRMS (calc.): 582.2855, (found): 582.2838 1B 714

NH₂ 4-{[4-Amino-6-(9H- fluoren-9-ylamino)- [1,3,5]triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR (acetone-d₆) δ (ppm):9.05-9.00 (m, 1H), 8.03-7.87 (m, 2H), 7.80-7.70 # (m, 2H), 7.63-7.20 (m,9H), 7.00 (t, 1H), 6.86 (d, 1H), 6.66 (t, 1H), 6.50-5.50 (m, 6H),4.75-4.55 (m, 3H). HRMS (calc.): 514.2229, (found): 514.2232 1B 8 15

NH₂ N-(2-amino-phenyl)-4-[(4- amino-6-piperidin-1-yl- [1,3,5]-triazin-2-ylamino)-methyl]- benzamide ¹H NMR (CDCl₃) δ (ppm): 7.96 (bs, 1H), 7.81(d, J=8.0 Hz, 2H), 7.38 (d, J=8.0 # Hz, 2H), 7.32 (d, J=8.0 Hz, 1H),7.08 (dt, J=7.7 Hz, 1.4 Hz, 1H), 6.83 (t, J=6.6 Hz, 2H), 5.47 (bs, 1H),4.80 (bs, 2H), 4.60 (d, J=6.0 Hz, 2H), 3.88 (bs, 2H), 3.67 (t, J=5.2 Hz,4H), 1.66-1.58 (m, 2H,), 1.56-1.48 (m, 4H). 1A 9 16

NH₂ 4-[(4-amino-6- cyclopentyl-amino- [1,3,5]-triazin-2-yl- amino)-methyl]-N-(2- amino-phenyl)- benzamide ¹H NMR (CDCl₃) δ (ppm): 7.97(bs, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.39-7.34 (m, # 3H), 7.10 (dt, J=7.6Hz, 1.4 Hz, 1H), 6.85 (t, J=7.0 Hz, 2H), 5.56 (bs, 1H), 4.90 (bs, 3H),4.62 (s, 2H), 4.25-4.19 (m, 1H) 3.88 (bs, 2H), 1.95 (m, 2H), 1.71-1.59(m, 4H), 1.43-1.37 (m, 2H). 1A 10 17

NH₂ (1R)-4-{[4-amino-6-(2- exo-fenchyl-amino)- [1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ(ppm): 9.08 (bs, 1H), AB system (δ_(A)=8.00, δ_(B)=7.51, # J=8.0 Hz,4H), 7.33 (bd, J=7.7 Hz, 1H), 7.03 (ddd, J=8.0 Hz, 7.3 Hz, 1.4 Hz, 1H),6.90 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.71 (dt, J=7.6 Hz, 1.4, 1H), 6.60-6.28(m, 1H), 5.80-5.20 # (m, 3H), 4.67 (bs, 4H), 3.87 (bd, J=9.1 Hz, 1H),1.80-1.60 (m, 4H), 1.56-1.42 (m, 1H), 1.34-1.00 (m including 2 s, 8H),0.84 (s, 3H). HRMS (calc.): 486.2855, (found): 486.2844 1A 11 18

4-{[4-allyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR (acetone-d₆) δ (ppm): 9.07(bs, 1H), 8.00 (bd, J=7.4 Hz, 2H), 7.58-7.42 (m, 2H), 7.34 (bd, J=8.0Hz, 1H), 7.27-7.10 # (m, 4H), 7.04 (td, J=7.6Hz, 1.5 Hz, 1H), 6.90 (dd,J=8.0, 1.4 Hz, 1H), 6.71 (dt, J=7.6 Hz, 1.4 Hz, 1H), 6.60-5.70 (m, 3H),5.26-5.00 (m, 2H), 4.86-4.54 (m, 4H), 4.10-3.90 (m, 2H), 3.38-3.10 (m,2H), 3.00-2.80 (m, 2H). HRMS (calc.): 506.2542, (found): 506.2533 1B 1219

4-{[4-cyclopropyl-amino- 6-(2-indanyl-amino)- [1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ(ppm): 9.07 (bs, 1H), 8.00 (bd, J=7.7 Hz, 2H), 7.60-7.40 (m, 2H), 7.33(dd, J=7.8 Hz, 1.3 Hz, # 1H), 7.28-7.10 (m, 4H), 7.04 (dt, J=7.6 Hz, 1.5Hz, 1H), 6.90 (dd, J=7.8 Hz, 1.4 Hz, 1H), 6.71 (dt, J=7.6 Hz, 1.3 Hz,1H), 6.67-5.80 (m, 2H), 4.90-4.50 (m, 4H), 3.40-3.10 (m, 2H), 3.05-2.70(m, 3H), 0.75-0.43 (m, 4H). HRMS (calc.): 506.2542, (found): 506.2548 1B13 20

NH₂ 4-[(4-Amino-6- phenethylamino- [1,3,5]triazin-2-ylamino)-methyl]-N-(2-amino- phenyl)-benzamide ¹H NMR (acetone-d₆) δ (ppm): 9.03(s, 1H), 7.97 (d, J=7.7 Hz, 2H), 7.55-7.40 (m, 2H), 7.35-7.10 (m, 6H),6.99 (td, J=8.0 Hz, # 1.3 Hz, 1H), 6.86 (dd, J=8.0 Hz, 1.3 Hz, 1H), 6.67(dt, J=8.0 Hz, 1.4 Hz, 1H), 6.62-5.40 (m, 5H), 4.75-4.45 (m, 3H),3.59-3.45 (m, 2H), 2.95-2.70 (m, 2H). HRMS (calc.): 454.2229, (found):454.2235 1A 14 21

NH₂ N-(2-Amino-phenyl)-4-{[4- amino-6-(3,4,5- trimethoxy- phenylamino)-methyl}-benzamide ¹H NMR (CDCl₃/MeOD) δ (ppm): 7.72 (d, J=8.2 Hz, 2H),7.21 (d, J=8.2 Hz, 2H), 7.04 (d, J=7.7 Hz, 1H), 6.91 (td, J=7.7 Hz, #1.2 Hz, 1H), 6.70-6.61 (m, 4H), 4.61 (bs, 2H), 3.58-3.52 (m, 9H). 1B 1522

NH₂ 4-{[4-Amino-6-(2,3- dihydro-indol-1-yl)- [1,3,5]triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR (CDCl₃/MeOD) δ (ppm): 8.06(bs, 1H), 7.82 (d, J=8.0 Hz, 2H), 7.37 (d, J=8.2 Hz, 2H), 7.13 (d, J=7.4Hz, 1H), 7.06 # (d, J=7.4 Hz, 1H), 7.02-6.96 (m, 2H), 6.84-6.71 (m, 3H),4.61 (bs, 2H), 4.03 (t, J=8.5 Hz, 2H), 3.02 (t, J=8.5 Hz, 2H). 1B 16 23

NH₂ 4-({4-Amino-6-[2-(2- methoxy-phenyl)- ethylamino]- [1,3,5]triazin-2-ylamino}-methyl)-N-(2- amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ(ppm): mixture of rotamers, 9.06 (s, 1H), 7.96 (d, J=8.0 Hz, 2H),7.55-7.40 (m, 2H), 7.28 (d, J=7.4 # Hz, 1H), 7.21-6.70 (m, 6H), 6.67 (t,J=7.4 Hz, 1H), 6.60-5.70 (m, 5H), 4.75-4.55 (m, 3H), 3.81 (s, 3H),3.55-3.45 (m, 2H), 2.90-2.78 (m, 2H). HRMS (calc.): 484.2335, (found):484.2331 1A 17 24

NH₂ 4-({4-Amino-6-[2-(2- fluoro-phenyl)- ethylamino]- [1,3,5]triazin-2-ylamino}-methyl)-N-(2- amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ(ppm): mixture of rotamers, 9.03 (s, 1H), 7.97 (d, J=8.0 Hz, 2H),7.55-7.40 (m, 2H), 7.38-7.17 (m, # 2H), 7.17-6.95 (m, 4H), 6.86 (dd,J=8.0 Hz, 1.4 Hz, 1H), 6.67 (t, J=7.0 Hz, 1H), 6.50-5.60 (m, 5H),4.75-4.55 (m, 3H), 3.60-3.52 (m, 2H), 2.95-2.85 (m, 2H). HRMS (calc.):472.2135, (found): 472.2146 1A 18 25

4-{[4-benzyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR (acetone-d₆) δ (ppm): 9.06(bs, 1H), 8.04-7.93 (m, 2H), 7.57-7.12 (m, 12H), 7.04 (td, J=7.6 Hz, 1.5Hz, 1H), # 6.91 (dd, J=8.0 Hz, 1.1 Hz, 1H), 6.72 (bt, J=7.6 Hz, 1H),6.68-5.90 (m, 3H), 4.84-4.50 (m, 7H), 3.35-3.13 (m, 2H), 3.00-2.80 (m,2H). HRMS (calc.): 556.2699, (found): 556.2706 1B 19 26

N-(2-Amino-phenyl)-4- [(4,6-di-piperidin-1-yl-[1,3,5]triazin-2-ylamino)- methyl]-benzamide ¹H NMR: (CDCl₃) δ (ppm):7.83 (d, J=8.2 Hz, 3H), 7.44 (d, J=8.2 Hz, 2H), 7.32 (d, J=7.4, 1H),7.12-7.06 (m, 1H), # 6.87-6.82 (m, 2H), 5.11 (t, J=6.2 Hz, 1H), 4.64 (d,J=6.3 Hz, 2H), 3.87 (bs, 2H), 3.69 (t, J=5.4 Hz, 8H), 1.63-1.53 (m,12H). 1B 20 27

4-{[6-(2-indanyl-amino)- 4-phenethyl-amino- [1,3,5]-triazin-2-ylamino]-methyl}-N-(2- amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ(ppm): 9.07 (bs, 1H), 8.05-7.90 (m, 2H), 7.60-7.40 (m, 2H), 7.35-7.05(m, 10H), 7.04 (td, J=7.6 Hz, # 1.5 Hz, 1H), 6.90 (d, J=7.7 Hz, 1H),6.71 (t, J=7.3 Hz, 1H), 6.60-5.70 (m, 3H), 4.95-4.50 (m, 5H), 3.70-2.80(m, 8H). HRMS (calc.): 552.2750 [M⁺ − NH₄], (found): 552.2746 1B 21 28

NH₂ 4-{[4-benzyl-amino-6-(2- indanyl-amino)-[1,3,5]- triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR (CDCl₃) δ (ppm): 7.83 (d,J=8.2 Hz, 3H), 7.44 (d, J=8.2 Hz, 2H), 7.32 (d, J=7.4, 1H), 7.12-7.06(m, 1H), # 6.87-6.82 (m, 2H), 5.11 (t, J=6.2 Hz, 1H), 4.64 (d, J=6.3 Hz,2H), 3.87 (bs, 2H), 3.69 (t, J=5.4 Hz), 1.63-1.53 (m, 12H). 1A 22 29

NH₂ 4-[(4-Amino-6- benzylamino- [1,3,5]triazin-2-ylamino)-methyl]-N-(2-amino- phenyl)-benzamide ¹H NMR (acetone-d₆) δ (ppm): 9.04(s, 1H), 7.95 (d, J=7.3 Hz, 2H), 7.45 (d, J=7.1 Hz, 2H), 7.38-7.15 (m,6H), 7.00 (td, # J=8.0 Hz, 1.5 Hz, 1H), 6.86 (dd, J=8.0 Hz, 1.4 Hz, 1H),6.67 (dt, J=8.0 Hz, 1.4 Hz, 1H), 6.67-6.25 (m, 3H), 5.85-5.55 (m, 3H),4.61 (d, J=6.3 Hz, 2H), 4.54 (d, J=5.2 Hz, 2H). HRMS (calc.): 440.2073,(found): 440.2078 1A 23 30

4-{[6-(2-indanyl-amino)- 4-(3-pyridinyl-methyl-amino)-[1,3,5]-triazin-2- ylamino]-methyl}-N-(2- amino-phenyl)-benzamide ¹H NMR (acetone-d₆) δ (ppm): mixture of rotamers, 9.20-9.00(m, 1H), 8.70-8.35 (m, 2H), 8.05-7.90 (m, 2H), 7.85-7.55 (m, # 1H),7.55-7.10 (m, 8H), 7.04 (dt, J=7.6 Hz, 1.5 Hz, 1H), 6.91 (bd, J=7.4 Hz,1H), 6.71 (bt, J=7.3 Hz, 1H), 6.80-6.00 (m, # 3H), 4.84-4.50 (m, 7H),3.34-3.12 (m, 2H), 3.00-2.80 (m, 2H). HRMS (calc.): 539.2546 [M⁺ − NH₄],(found): 539.2533 1B 24 31

N-(2-Amino-phenyl)-4-[(4- piperidin-1-yl-6- pyrrolidin-1-yl-[1,3,5]triazin-2-ylamino)- methyl]-benzamide ¹H NMR (CDCl₃) δ (ppm):7.89 (bs, 1H,), 7.82 (d, J=8.2 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.32 (d,J=8.0 Hz, 1H), 7.09 (dt, # J=7.7 Hz, 1.6 Hz, 1H), 6.87-6.82 (m, 2H),4.83 (bs, 1H), 4.62 (d, J=6.0 Hz, 2H), 4.24 (m, 1H), 3.88 (bs, 1H),2.04-1.96 (m, 2H), 1.70-1.52 (m, 10H), 1.46-1.38 (m, 2H). 1B 25 32

N-(2-Amino-phenyl)-4-{[2- piperidin-1-yl-6-(2- pyrrolidin-1-yl-ethylamino)-pyrimidin-4- ylamino]-methyl}- benzamide ¹H NMR (CDCl₃) δ(ppm): 8.27 (bs, 1H), 7.74 (d, J=7.4 Hz, 2H), 7.29 (m, 3H), 7.05 (dt,J=7.6 Hz, 1.4 Hz, # 1H), 6.81-6.76 (m, 2H), 5.62 (bs, 2H), 4.57 (bs,2H), 3.91 (bs, 2H), 3.69 (m, 4H), 3.45 (m, 2H), 2.57 (t, J=6.2 Hz, 2H),2.47 (m, 4H), 1.71 (m, 4H), 1.59-1.50 (m, 6H). 1B 26 33

4-{[6-(2-indanyl-amino)- 4-morpholin-4-yl-[1,3,5]- triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-benzamide ¹H NMR (acetone-d₆) δ (ppm): 9.07(bs, 1H), 8.08-7.95 (m, 2H), 7.60-7.43 (m, # 2H), 7.33 (d, J=8.0 Hz,1H), 7.28-7.12 (m, 4H), 7.04 (dt, J=7.6 Hz, 1.4 Hz, 1H), 6.91 (d, J=7.4Hz, 1H), 6.72 (t, J=7.4 Hz, # 1H), 6.55-6.05 (m, 2H), 4.86-4.60 (m, 5H),3.80-3.56 (m, 8H), 3.38-3.12 (m, 2H), 3.04-2.82 (m, 2H). 1B 27 34

N-(2-Amino-phenyl)-4-{[2- piperidin-1-yl-6-(2- pyrrolidin-1-yl-ethylamino)-pyrimidin-4- ylamino]-methyl}- benzamide ¹H NMR (acetone-d₆)δ (ppm): 9.08 (bs, 1H), 8.01 (bd, J=7.4 Hz, 2H), 7.56-7.43 # (m, 2H),7.33 (bd, J=8.0 Hz, 1H), 7.28-7.12 (m, 4H), 7.04 (dt, J=7.6 Hz, 1.4 Hz,1H), 6.90 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.71 (dt, J=7.6 Hz, 1.4 Hz, 1H),6.65-5.75 (m, 2H), 4.90-4.58 (m, 5H), 3.66-2.34 (m, 16H). 1B 28 35

NH₂ 4-({4-Amino-6-[2-(1H- indol-3-yl)-ethylamino]- [1,3,5]triazin-2-ylamino}-methyl)-N-(2- amino-phenyl)- benzamide ¹H NMR (acetone-d₆) δ(ppm): 10.00 (s, 1H), 9.13 (s, 1H), 7.93 (d, J=8.0 Hz, 2H), 7.70-7.50(m, 1H), 7.50-7.22 # (m, 4H), 7.18-6.91 (m, 4H), 6.85 (d, J=7.1 Hz, 1H),6.67 (t, J=7.4 Hz, 1H), 6.40-5.90 (m, 3H), 4.75-4.50 (m, 2H), 4.37 (s,2H), 3.62 (d, J=6.3 Hz, 2H), 2.99 (s, 2H). 1A

[0307] TABLE 2b

Ex. Cpd X Y Name Characterization Schm 329 470

NH₂ 4-{[4-amino-6-(3- phenyl-propyl-1-amino)- [1,3,5]triazin-2-yl-amino]-methyl}-N- (2-amino-phenyl)- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.03 (s, 1H), 7.96 (d, J=8.2 Hz, 2H), # 7.46 (d,J=7.7 Hz, 2H), 7.35-7.10 (m, 6H), 7.00 (t, J=7.7 Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 6.67 (t, J=7.7 Hz, 1H), 6.60-5.40 (m, 6H), 4.62 (s, 2H), 3.35(dd, J=12.1, 6.9 Hz, 2H), 2.75-2.60 (m, 2H), 1.95-1.80 (m, 2H). 1A 330471

N-(2-amino-phenyl)-4- [(4-cyclopropyl-amino-6- phenethyl-amino-[1,3,5]triazin-2-yl- amino)-methyl]- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.04 (s, 1H), 7.96 (d, J=8.0 Hz, # 2H), 7.55-7.40(m, 2H), 7.35-7.10 (m, 6H), 6.98 (t, J=7.4 Hz, 1H), 6.85 (d, J=6.9 Hz,1H), 6.66 (t, J=7.3 Hz, 1H), 6.20-5.50 (m, 3H), 4.80-4.50 (m, 4H),3.65-3.45 (m, 2H), 3.00-2.60 (m, 2H), 0.80-0.40 (m, 4H). 1B 331 472

N-(2-amino-phenyl)-4- {[4-cyclopropyl-methyl- amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2- yl-amino]-methyl}- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.06 (bs, 1H), 8.00 (bd, J=7.1, 2H), # 7.50 (bs,1H), ), 7.33 (d, J=6.6 Hz, 1H), 7.28-7.07 (m, 4H), 7.03 (td, J=7.6, 1.5Hz, 1H), 6.90 (dd, J=8.0, 1.4 Hz, 1H), 6.71 (td, J=7.6, 1.4 Hz, 1H),6.55-5.70 (m, 3H), 4.90-4.50 (m, 5H), 3.40-2.80 (m, 6H), 1.07 (bs, 1H),0.44 (bs, 2H), 0.23 (bs, 2H). 1B 332 473

n-BuNH N-(2-amino-phenyl)-4- [(4-n-butyl-amino-6- phenethyl-amino-[1,3,5]triazin-2-yl- amino)-methyl]-benzamide ¹H NMR (300 MHz, CDCl₃) δ(ppm): 8.08 (s, 1H), 7.83 (d, J=6.6 Hz, 2H), 7.45-7.05 (m, 8H), 7.08(td, J=7.8, 1.5 Hz, # 1H), 6.84 (t, J=8.1 Hz, 2H), 6.70-5.00 (m, 3H),4.70-4.50 (m, 2H), 3.65-3.50 (m, 2H), 3.45-3.25 (m, 2H), 2.40-2.25 (m,2H), 1.60-1.45 (m, 2H), 1.45-1.00 (m, 2H), 1.00-0.8 (m, 3). 1B 333 474

MeOCH₂CH₂NH N-(2-amino-phenyl)-4- {[4-(2-methoxy-ethyl-1-amino)-6-phenethyl- amino-[1,3,5]triazin-2-yl- amino]-methyl}- benzamide¹H NMR (300 MHz, acetone-d₆) δ (ppm): 9.02 (s), 8.58 (s), 8.40 (dd,J=7.2, 2 Hz, 1H), 7.97 (d, # J=7.5 Hz, 1H), 7.51-7.40 (m, 2H), 7.70-6.90(m, 7H), 6.86 (dd, J=8.1, 1.2 Hz), 6.76 (dd, J=7.5, 1.8 Hz), 6.67 (td,J=7.8, 1.5 Hz), 6.60-5.50 (m, 3H), 4.75-4.55 (m, 4H), 3.65-3.35 (m, 6H),3.35-3.20 (s, 3H), 2.95-2.75 (m, 2H). 1B 334 475

N-(2-amino-phenyl)-4- {[4-(4-chloro-phenethyl- amino)-6-cyclopropyl-amino-[1,3,5]triazin-2-yl- amino]-methyl}- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.02 (s, 1H), 8.02-7.91 (m, 2H), # 7.58-7.40 (m,2H), 7.28 (s, 4H), 7.20-7.05 (m, 1H), 6.99 (td, J=7.5, 1.8 Hz, 1H), 6.86(d, J=7.8 Hz, 1H), 6.67 (t, J=6.9 Hz, 1H), 6.60-5.60 (m, 3H), 4.75-4.50(m, 4H), 3.65-3.40 (bs, 2H), 2.95-2.65 (m, 2H), 0.75-0.55 (m, 2H),0.55-0.40 (m, 2H). 1B 335 476

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(4-methoxy-phenethyl-amino)-[1,3,5]triazin-2- yl-amino]-methyl}- benzamide ¹H NMR (300 MHz,CDCl₃) δ (ppm): 8.55-7.72 # (m, 4H), 7.55-6.75 (m, 9H), 6.75-5.30 (m,3H), 4.69 (m, 2H), 3.85 (s, 3H), 3.63 (bs, 2H), 2.86 (m, 3H), 0.85 (bs,2H), 0.61 (bs, 2H). 1B 336 477

N-(2-amino-phenyl)-4- {[4-(3-chloro-phenethyl- amino)-6-cyclopropyl-amino-[1,3,5]triazin-2-yl- amino]-methyl}- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.03 (s, 1H), 7.96 (d, J=7.5 Hz, 2H), 7.60-7.37 (m,2H), 7.37-7.12 # (m, 5H), 6.99 (t, J=6.9 Hz, 1H), 6.86 (d, J=6.9 Hz,1H), 6.67 (t, J=7.2 Hz, 1H), 6.60-5.60 (m, 3H), 4.75-4.50 (m, 4H),3.67-3.45 (m, 2H), 3.00-2.67 (m, 3H), 0.75-0.40 (m, 4H). 1B 337 478

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(3,4-dimethoxy-phenethyl-amino)- [1,3,5]triazin-2-yl- amino]-methyl}- benzamide ¹H NMR(300 MHz, acetone-d₆) δ (ppm): 9.02 (s, 1H), 7.96 (d, J=8.1 Hz, 2H),7.60-7.40 (m, 2H), 7.29 (d, # J=8.1 Hz, 1H), 6.99 (td, J=8.1, 1.5 Hz,1H), 6.95-6.72 (m, 4H), 6.67 (td, J=7.8, 1.5 Hz, 1H), 6.20-5.60 (m, 3H),4.78-4.52 (m, 4H), 3.75 (s, 6H), 3.65-3.42 (m, 2H), 2.95-2.65 (m, 3H),0.72-0.40 (m, 4H). 1B 338 479

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(3-methoxy-phenethyl-amino)-[1,3,5]triazin-2- yl-amino]-methyl}- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.02 (s, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.60-7.35 (m,2H), 7.29 (d, # J=7.5 Hz, 1H), 7.18 (t, J=7.8 Hz, 1H), 6.99 (td, J=7.5,1.5 Hz, 1H), 6.90-6.70 (m, 4H), 6.67 (t, J=7.8 Hz, 1H), 6.60-5.60 (m,3H), 4.77-4.50 (m, 4H), 3.76 (s, 3H), 3.65-3.45 (m, 2H), 2.92-2.65 (m,3H), 0.72-0.42 (m, 4H). 1B 339 480

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(2-pyridin-2-yl-ethyl-1-amino)-[1,3,5]triazin- 2-yl-amino]-methyl}- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.03 (s, 1H), 8.50 (d, J=1.2 Hz, 1H), 7.96 (d,J=8.1 Hz, 2H), # 7.66 (t, J=7.5 Hz, 1H), 7.60-7.40 (m, 2H), 7.35-7.08(m, 3H), 6.99 (td, J=8.1, 1.5 Hz, 1H), 6.86 (dd, J=8.1, 1.5 Hz, 1H),6.67 (td, J=7.8, 1.5 Hz, 1H), 6.60-5.60 (m, 3H), 4.75-4.50 (m, 4H),3.80-3.60 (m, 2H), 3.15-2.90 (m, 2H),2.90-2.65 (m, 1H), 0.73-0.40 (m,4H). 1B 340 481

N-(2-amino-phenyl)-4- {[6-cyclopropyl-amino- 4-(3-pyridin-2-yl-ethyl-1-amino)-[1,3,5]triazin- 2-yl-amino]-methyl}- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.20-9.00 (m, 1H), 8.70-8.50 (m, 2H), 8.00 and 7.88(2d, J=7.9 Hz, # 2H), 7.75-7.43 (m, 3H), 7.38-6.67 (m, 5H), 6.22-5.78(m, 3H), 4.80-4.55 (m, 4H), 3.61 (bs, 2H), 3.20-2.65 (m, 3H), 0.80-0.45(m, 4H). 1B 341 482

N-(2-amino-phenyl)-4- [(4-cyclopropyl-amino- 6-phenethyl-oxy-[1,3,5]triazin-2-yl- amino)-methyl]- benzamide ¹H NMR (300 MHz,acetone-d₆) δ (ppm): 9.04 (s, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.60-7.40 (m,2H), 7.35-7.15 (m, 6H), 7.00 (td, # J=7.5, 1.5 Hz, 1H), 6.86 (d, J=8.1Hz, 1H), 6.67 (t, J=7.5 Hz, 1H), 7.18-6.35 (m, 2H), 4.75-4.30 (m, 6H),3.10-2.92 (m, 2H), 0.75-0.63 (m, 2H), 0.57-0.48 (m, 2H). 1, 25 342 483

Me N-(2-amino-phenyl)-4- [(6-methyl-4-phenethyl- amino-[1,3,5]triazin-2-yl-amino)-methyl]- benzamide ¹H NMR (300 MHz, acetone-d₆ +

DMSO-d₆) δ (ppm): mixture of rotamers, 9.62 (bs, 1H), 8.03 (d, J=8.0 Hz,2H), 7.80-7.44 (m, 3H), # 7.40-7.10 (m, 8H), 7.01 (t, J=7.6 Hz, 1H),6.87 (d, J=7.9 Hz, 1H), 6.67 (t, J=7.4 Hz, 1H), 4.85 (bs, 2H), 4.72-4.54(m, 2H), 3.63-3.42 (m, 2H), 2.96-2.74 (m, 2H), 2.21 and 2.13 (2s, 3H).30 343 484

NH₂ N-(2-amino-phenyl)-4- {[4-amino-6-phenyl- [1,3,5]-triazin-2-yl-amino]-methyl}- benzamide ¹H NMR (300 MHz, acetone-d₆) δ (ppm): mixtureof rotamers, 9.08 (bs, 1H), 8.48-8.36 (m, 2H), 8.02 (d, J=8.2 Hz, 2H),7.63-7.42 (m, 5H), 7.33 # (d, J=7.7 Hz, 1H), 7.19 (bs, 1H), 7.03 (t,J=7.4 Hz, 1H), 6.88 (d, J=7.9 Hz, 1H), 6.70 (t, J=7.6 Hz, 1H), 6.35 and6.25 (2bs, 2H), 4.87 and 4.75 (2d, J=5.9 Hz, 2H), 4.65 (bs, 2H). 30 344485

N-(2-amino-phenyl)-4- {[6-(2-indanyl-amino)-4- phenyl-[1,3,5]-triazin-2-yl-amino]-methyl}- benzamide ¹H NMR (300 MHz, acetone-d₆) δ (ppm):mixture of rotamers, 9.14-8.96 (m, 1H), 8.54-8.30 (m, 2H), 8.09-7.95 (m,2H), 7.68-7.40 # (m, 5H), 7.38-7.08 (m, 6H), 7.03 (t, J=7.3 Hz, 1H),6.94-6.76 (m, 2H), 6.71 (t, J=7.3 Hz, 1H), 5.13-4.54 (m, 5H), 3.49-3.18(m, 2H), 3.12-2.90 (m, 2H). 30

[0308]

Example 29N-(2-Amino-phenyl)-4-({4-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino}-methyl)-benzamide(compound 39)

[0309] Step 1: N-Acetyl-1-piperonylpiperazine (compound 37)

[0310] To a stirred solution at 0° C. of 1-piperonylpiperazine 36 (5.00g, 22.7 mmol) in anhydrous CH₂Cl₂ (60 mL) was added Et₃N (6.33 mL, 45.4mmol) followed by acetyl chloride (1.94 mL, 27.2 mmol). The reactionmixture was stirred 30 min. at 0° C. and then 2 h at room temperature.The reaction mixture was poured into a saturated aqueous solution ofNH₄Cl, and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 4/96) to afford thetitle compound 37 (5.52 g, 21.11 mmol, 93% yield) as a yellow solid. ¹HNMR: (300 MHz, CDCl₃) δ(ppm): 6.83 (s, 1H), 6.72 (m, 2H), 5.92 (s, 2H),3.59 (t, J=5.1 Hz, 2H), 3.44-3.40 (m, 4H), 2.42 (dt, J=5.1 Hz, 4H), 2.06(s, 3H).

[0311] Step 2:2-Chloro-4-morpholin-4-yl-6-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-[1,3,5]triazine(compound 38)

[0312] To a stirred solution of 37 (3.00 g, 11.4 mmol) in anhydrous THF(25 mL) at −78° C. was slowly added a solution of LiHMDS (11.4 mL, 11.4mmol, 1 M in THF). The reaction mixture was stirred 1 h at −78 ° C. anda solution of 2,4-dichloro-6-morpholin-4-yl-[1,3,5]triazine (2.69 g,11.4 mmol) in anhydrous THF (25 mL) was added. The reaction mixture wasslowly warmed up at room temperature and the reaction was quenched after16 h with a saturated aqueous solution of NH₄Cl. The THF was evaporatedand the residue was diluted with AcOEt. The organic layer wassuccessively washed with sat. NH₄Cl and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 1/99→3/97) to affordthe title compound 38 (4.84 g, 10.49 mmol, 92% yield) as a pale yellowsolid. ¹H NMR (300 MHz, CDCl₃) δ(ppm): 6.84 (s, 1H), 6.77-6.69 (m, 2H),5.95 (s, 2H), 3.75-3.43 (m, 16H), 2.42 (m, 4H).

[0313] Step 3:N-(2-Amino-phenyl)-4-({4-[2-(4-benzo[1,3]dioxol-5-ylmethyl-piperazin-1-yl)-2-oxo-ethyl]-6-morpholin-4-yl-[1,3,5]triazin-2-ylamino}-methyl)-benzamide(compound 39)

[0314] The title compound 39 was obtained following the same procedureas Example 1, step 5. ¹H NMR (CDCl₃) δ(ppm): 7.96 (bs, 1H), 7.87 (d,J=8.2 Hz, 2H), 7.39 (d, J=8.2 Hz, 2H), 7.33 d, J=8.5 Hz, 1H), 7.10 (dt,J=7.6 Hz, 1.2 Hz, 1H), 6.87-6.81 (m, 3H), 6.75-6.68 (m, 2H), 5.93 (s,2H), 5.67 (bs, 1H), 4.64 (s, 2H), 3.90 (bs, 2H), 3.75-3.35 (m, 16H),2.45-2.30 (m, 4H).

Example 40 N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide(compound 44)

[0315] Step 1: N-(5-Bromo-pyridin-2-yl)-N′-phenyl-ethane-1,2-diamine(compound 42)

[0316] A mixture of 2,5-dibromopyridine 40 (2.08 g, 8.6 mmol) andphenyl-1,2-ethyldiamine (1.98 g, 14.6 mmol, 1.7 equiv.) was stirredunder nitrogen at 120° C. for 6 h. After cooling down to roomtemperature, the solid mixture was ground in a mortar, dissolved inethyl acetate (200 mL), washed with saturated NaHCO₃ (2×50 mL), dried(MgSO₄), filtered and concentrated. After a quick purification through ashort chromatographic column (silica gel, elution 50% ether in hexanes),a pale yellow solid 42 (1.75 g, 6.01 mmol, 70% yield) was obtained. ¹³CNMR (300 MHz, acetone-d₆) δ(ppm): 158.6, 149.6, 148.8, 139.9, 129.8,117.1, 113.1, 110.8, 106.6, 43.9, 41.5. LMRS=294.0 (M+1).

[0317] Step 2:N-(2-aminophenyl)-6-(2-phenylamino-ethylamino)-nicotinamide (compound44)

[0318] A mixture of 5-bromo-2-N-alkanyl-2-aminopyridine 42 (352 mg, 1.2mmol), 1,2-phenylenediamine (3.95 mmol, 3.3 equiv.), Pd(OAc)₂ (0.31mmol, 26% mol) and 1,1′-bis(diphenylphosphino)ferrocene (124 mg, 0.22mmol) was suspended in degassed DMF (3 mL), treated withdiisopropylethyl amine (0.9 mL, 5.2 mmol) and the system flushed withCO. The reaction mixture was warmed up to 60° C. and stirred under CO(balloon) for 18 h at this temperature. After evaporation of the DMFunder vacuo, the residue was purified through a chromatographic column(silica gel, elution 3% to 6% methanol in dichloromethane) to give 258mg (0.74 mmol, 62% yield) of the aminoanilide 44. ¹H-NMR (CD₃OD-d4),δ(ppm): 8.67 (d, J=2.2 Hz, 1H), 7.97 (dd, J=8.9 Hz, 2.5 Hz, 1H), 7.58(m, 1H), 7.51 (m, 1H), 7.15 (dd, J=7.7 Hz, 1.1 Hz, 1H), 7.08 (m, 2H),6,89 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.76 (dt, J=7.7 Hz, 4.4 Hz, 1H), 6.67(t, J=7.7 Hz, 2H), 6.60 (m, 2H), 4.87 (bs, 4H), 3.60 (t, J=6.3 Hz, 2H),3.35 (t, J=6.3 Hz, 2H).

Example 41 N-(2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide(compound 45)

[0319] Step 1: N-(5-Bromo-pyridin-2-yl)-4-methoxybenzylamine (compound43)

[0320] A mixture of 2,6-dibromopyridine 41 (6.03 mmol, 2 equiv.) andpara-methoxybenzyl amine (413 mg, 3.01 mmol) was stirred under nitrogenat 120° C. for 6 h. After identical work-up procedure described beforeand purification through a pad of silica gel (elution 50% ether inhexanes), a pale yellow solid 43 (773 mg, 2.60 mmol, 87% yield) wasobtained. ¹³C NMR (300 MHz, CDCl₃) δ(ppm): 159.1, 139.7, 132.1, 130.5,128.9, 127.2, 116.2, 114.3, 104.8, 55.4, 46.0. LMRS=295.0 (M+1).

[0321] Step 2: N-(2-amino-phenyl)-6-(4-methoxy-benzylamino)-nicotinamide(compound 45)

[0322] Following the procedure described in Example 40, step 2, butsubstituting 43 for 42, the title compound 45 was obtained in 61% yield.

Example 42N-(2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-acrylamide(compound 50)

[0323] Step 2: 3-[6-(2-Phenylamino-ethylamino)-pyridin-3-yl)-acrylicacid tert-butyl ester (compound 46)

[0324] In a 50 mL flask, a mixture of 42 (308 mg, 1.05 mmol),tert-butylacrylate (0.8 mL, 5.5 mmol), diisopropylethylamine (0.8 mL,4.6 mmol), tri-o-tolylphosphine (POT, 192 mg, 0.63 mmol), Pd₂(dba)₃ (73mg, 0.08 mmol) in anhydrous DMF (4 mL) was stirred at 120° C. (preheatedoil bath) for 2 h under nitrogen. After DMF removal, the crude residuewas submitted to a chromatographic purification (column silica gel, 50%ether in hexanes) to afford 316 mg of 46 (88% yield). ¹³C NMR (300 MHz,CDCl₃) δ(ppm): 166.6, 159.3, 149.6, 147.8, 140.7, 134.9, 129.1, 119.8,117.3, 115.9, 112.6, 107.8, 80.0, 43.5, 40.9, 28.1. LRMS=340.3 (M+1).

[0325] Step 3: 3-[6-(2-Phenylamino-ethylamino)-pyridin-3-yl)-acrylicacid (compound 48)

[0326] Ester 46 (0.93 mmol) was dissolved 40% TFA in dichloromethane (10mL) and the solution stirred at room temperature overnight. The solventwas removed under vacuo distilling with acetonitrile (3×10 mL) andstored under high vacuum for 6 h. The solid residue 48 was employed forthe next reaction without further purification. LRMS=284.1 (M+1).

[0327] Step 4:N-(2-aminophenyl)-3-[6-(2-phenylamino-ethylamino)-pyridin-3-yl]-acrylamide(compound 50)

[0328] A mixture of acid 48 (0.93 mmol), BOP (495 mg, 1.12 mmol) and1,2-phenylenediamine (124 mg, 1.15 mmol) were dissolved in dryacetonitrile (4 mL) and treated with triethylamine (0.8 mL, 5.7 mmol).The solution was stirred under nitrogen at room temperature for 16 h.After concentration under vacuo, the crude was purified throughchromatographic column (5% methanol in dichloromethane), then wascrystallized from chloroform to give 50 (247 mg, 71% yield). ¹H-NMR(DMSO-d6), δ(ppm): 9.25 (bs, 1H), 8.21 (d, J=1.6 Hz, 1H), 7.67 (d, J=8.5Hz, 1H), 7.43 (d, J=15.7 Hz, 1H), 7.32 (d, J=7.4 Hz, 1H), 7.24 (t, J=1.0Hz, 1H), 7.08 (t, J=7.4 Hz, 2H), 6.91 (t, J=8.0 Hz, 1H), 6.75 (dt, J=8.0Hz, 0.4 Hz, 1H), 6.57 (m, 6H), 5.20 (bs, 1H), 3.48 (t, J=6.3 Hz, 2H),3.33 (bs, 2H), 3.21 (t, J=6.3 Hz, 2H).

Example 43N-(2-aminophenyl)-3-[6-(4-methoxy-benzylamino)-pyridin-2-yl]-acrylamide(compound 51)

[0329] Step 2:N-(2-aminophenyl)-3-[6-(4-methoxy-benzylamino)-pyridin-2-yl]-acrylamide(compound 51)

[0330] Following the procedure described in Example 42, steps 2, 3, 4,but substituting 43 for 42, the title compound 51 was obtained in 50%yield (on 2 steps). ¹H-NMR (CDCl₃), δ(ppm): 7.60 (bs, 1H), 7.55 (bs,1H), 7.43 (t, J=7.7 Hz, 1H), 7.29 (d, J=8.3 Hz, 2H), 7.17 (d, J=15.1 Hz,1H), 7.06 (t, J=7.7 Hz, 1H), 6.88 (d, J=8.3 Hz, 2H), 6.80 (m, 2H), 6.70(m, 3H), 6.41 (d, J=8.5 Hz, 1H), 4.50 (d, J=5.5 Hz, 2H), 3.80 (s, 3H),3.45 (bs, 2H).

Example 44 4-[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamic acidpyridin-3-yl methyl ester (compound 55)

[0331] Step 1: (4-bromo-benzyl)-carbamic acid pyridin-3-yl-methyl ester(compound 54)

[0332] 4-bromobenzylamine HCl (3.0 g, 13.4 mmol) was dissolved in DMF(60 mL) at rt and then Et₃N (4.13 mL, 29.7 mmol) was added dropwise over10 min to give cloudy solution. To this, DBU (2.42 mL, 16.2 mmol) and1,1′-carbonyl diimidazole (2.41 g, 14.8 mmol) were added. After beingstirred for 1 h at rt, 3-pyridylcarbinol (1.44 mL, 14.8 mmol) was addeddropwise over 10 min. The resulting reaction mixture was stirredovernight and then concentrated under reduced pressure. The residueobtained was diluted with ether/EtOAc (9:1) and then washed with H₂O.The organic layer was dried over Na₂SO₄, filtered and then concentratedto give the crude product which was recrystallized from EtOAc to give2.55 g of product 54 (59% yield, LRMS=323 (M+1).

[0333] Step 2: 4-[2-(2-amino-phenylcarbamoyl)-vinyl]-benzyl}-carbamicacid pyridin-3-yl methyl ester (compound 55)

[0334] Following the procedure described in Example 42, steps 2, 3, butsubstituting 54 for 42, and acrylic acid for tert-butyl acrylate thetitle compound 55 was obtained in an overall yield of 20%. ¹H NMR:(DMSO-d6) δ(ppm): 10.03 (s, 1H), 9.32 (s, 1H), 8.65 (s, 1H), 8.55 (d,J=3.3 Hz, 1H), 7.85 (d, J=7.69 Hz, 1H), 7.40-7.60 (m, 6H), 7.31 (d,J=7.69 Hz, 1H), 6.89 (dd, J=7.14 Hz, J=7 Hz, 1H), 6.71-6.79 (m, 2H),6.55 (dd, J=7.1 Hz, J=7 Hz, 1H), 5.20 (s, 2H), 4.93 (bs, 2H).

Example 45N-(2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide(compound 59)

[0335] Step 1: (4-Bromo-benzyl)-(3,4,5-trimethoxy-benzyl)-amine(compound 57)

[0336] To a stirred suspension of K₂CO₃ (522 mg, 3.77 mmol) in dry DMFwas added 3,4,5-trimethoxybenzylamine (1.10 mL, 6.44 mmol, 2.2 equiv.)followed by a solution of p-bromo benzylbromide (0.73 g, 2.91 mmol) indry DMF (8 mL). The mixture was stirred at room temperature undernitrogen for two days in the dark, diluted with dichloromethane (200mL), washed with brine, dried (MgSO4), filtered and concentrated. Thecrude residue was purified by chromatographic column on silica gel(elution 5% methanol in dichloromethane) to give 2.59 mmol (89% yield)of dibenzylamine 57. ¹³C NMR (300 MHz, CDCl₃) δ(ppm): 152.5, 138.8,136.1, 135.4, 130.6, 129.2, 119.8, 104.2, 59.9, 55.3, 52.6, 51.7.LRMS=368.4 (M+1).

[0337] Step 2:N-(2-Nitro-phenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide(compound 58)

[0338] Preparation of the Nitroacrylanilide

[0339] To a mixture of 2-nitroaniline (1.73 g, 12.5 mmol), DMAP (321 mg,2.6 mmol) and 2,6-di-tert-butyl-4-methylphenol (308 mg) in drydichloromethane (50 mL) at 0° C. was added triethylamine (10.6 mL, 76mmol) followed by acryloylchloride (3.2 mL, 38 mmol, 3.0 equiv.), andthe mixture was stirred at room temperature for 16 h. The solution wasdiluted with dichloromethane (250 mL), cooled to 0° C. and the excess ofreagent quenched with saturated NaHCO₃ (stirring for 1 h). The organiclayer was then washed (5% KHSO₄, then brine), dried (MgSO₄), filteredand concentrated under reduced pressure. After purification throughchromatographic column on silica gel (elution 50% ether in hexanes), 642mg (3.34 mmol, 27% yield) of the amide was obtained. ¹³C NMR (300 MHz,CDCl₃) δ(ppm): 163.6, 136.0, 135.6, 134.5, 131.3, 128.6, 125.4, 123.1,121.8. LRMS=193.2 (M+1).

[0340] Step 3:N-(2-aminophenyl)-3-{4-[(3,4,5-trimethoxy-benzylamino)-methyl]-phenyl}-acrylamide(59)

[0341] A mixture of nitro-compound 58 (127 mg, 0.27 mmol), SnCl₂ (429mg, 2.26 mmol, 8.4 equiv.) and NH₄OAc (445 mg) was suspended in methanol(9.5 mL) and water (1.5 mL), and the mixture was heated at 70° C. for 45min. The mixture was diluted with ethylacetate (100 mL) and washed withbrine and then saturated NaHCO₃, dried (MgSO₄), filtered, andconcentrated. Purification by chromatographic column on silica gel(elution 5 to 10% methanol in dichloromethane) gave 52 mg (43% yield) of59. ¹H-NMR (CDCl₃), δ(ppm): 8.25 (bs, 1H), 7.59 (d, J=15.6 Hz, 1H), 7.38(d, J=7.5 Hz, 2H), 7.29 (d, J=7.5 Hz, 2H), 7.25 (m 1H), 7.02 (t, J=6.8Hz, 1H), 6.75 (m, 2H), 6.62 (d, J=15.6 Hz, 1H), 6.58 (s, 2H), 3.97 (bs,3H), 3.80 (s, 9H), 3.78 (s, 2H), 3.72 (s, 2H).

Example 46N-(2-aminophenyl)-3-(4-{[(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-acrylamide(compound 61)

[0342] Step 1:3-{4-{[Methyl-(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-N-(2-nitro-phenyl)acrylamide(compound 60)

[0343] Amine 58 (180.2 mg, 0.38 mmol) was dissolved in 88% of HCO₂H (6mL), treated with excess of paraformaldehyde (7.67 mmol) and the mixturestirred at 70° C. for 2.5 h. A saturated NaHCO₃ solution, was addedslowly, extracted with dichloromethane (2×75 mL), dried (MgSO₄),filtered and concentrated. After chromatographic column on silica gel(elution 3 to 5% methanol in dichloromethane), pure N-methyl amine 60(118 mg, 63% yield) was obtained. ¹³C NMR (300 MHz, CDCl₃) δ(ppm):164.5, 153.1, 143.5, 142.3, 136.8, 136.1, 136.0, 135.3, 134.9, 132.9,129.3, 128.2, 125.8, 123.1, 122.2, 120.3, 105.4, 62.2, 61.2, 60.8, 56.0,42.5. LRMS=492.5 (M+1).

[0344] Step 2:N-(2-aminophenyl)-3-(4-{[(3,4,5-trimethoxy-benzyl)-amino]-methyl}-phenyl)-acrylamide(compound 61)

[0345] Following the procedure described in Example 45, step 3, butsubstituting the nitro-compound 60 for 58, the title compound 61 wasobtained in 72% yield. ¹H-NMR (DMSO-d6), δ(ppm): 9.15 (bs, 1H), 8.13(bs, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.30 (m 4H), 7.12 (d, J=7.7 Hz, 1H),6.91 (m 3H), 6.75 (d, J=7.8 Hz, 1H), 6.57 (m 2H), 4.83 (bs, 2H), 4.43(d, J=5.5 Hz, 2H), 3.72 (s, 3H), 3.33 (s, 3H).

Example 47N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylamide(compound 65)

[0346] Step 1: Methyl-3-(4-amino-phenyl)-acrylate hydrochloride(compound 63)

[0347] 4-amino-cinnamic acid (10.41 g, 0.052 mol) was dissolved inmethanol (100 mL) at rt. A solution of HCl in dioxane (15.6 mL, 4 N) wasthen added. The reaction mixture was heated at reflux overnight. Theclear solution was evaporated to a half volume and then settled down atrt. The white suspension obtained was collected by vacuum filtration.The mother liquid was evaporated again to a quart volume and cooled downto rt. The suspension was filtered again. The combined the solidcollected from two filtration was dried in vacuo to give 7.16 g of 63(64.3% yield). LRMS: 178 (M+1).

[0348] Step 2: Methyl-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylatehydrochloride (compound 64)

[0349] To a suspension of compound 63 (3.57 g, 16.7 mmol) in DMF (30 mL)was added Et₃N. after 10 min 4-methoxybenzyl chloride (2.0 g, 12.8mmol), Nal (0.38 g, 2.6 mmol) and K₂CO₃ (3.53 g, 25.5 mmol) were addedsuccessively. The mixture was heated at 60° C. overnight and evaporatedto dryness. The residue was partitioned between NaHCO₃ sat. solution (50mL) and EtOAc (50 mL×3). The combined organic layers were washed withbrine and then evaporated to dryness. The residue was purified by flashchromatography and then recrystallized from isopropylalcohol to give1.16 g 64 (yield 30.6%, LRMS=298) and 1.46 g of 63 (49% recoveredyield).

[0350] Step 3:N-(2-aminophenyl)-3-{4-(4-methoxy-benzylamino)-phenyl}-acrylamide(compound 65)

[0351] Following the procedure described in Example 42, step 4, butsubstituting 64 for 48, the title compound 65 was obtained in 32% yield.¹H NMR: (DMSO-d6) δ(ppm): 9.15 (s, 1H), 7.24)-7.38 (m, 6H), 6.84-6.90(m, 3H), 6.72 (m, 2H), 6.49-6.60 (m, 4H), 4.84 (s, 2H), 4.22 (d, J=5.77Hz, 2H).

Example 48 N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide(compound 71)

[0352] Step 1: N-(4-Iodo-phenyl)-(3-phenyl-allyl)-amine (compound 69)

[0353] Following the procedure described in Example 47, step 2, butsubstituting 68 for 63, the title compound 69 was obtained in 70% yield.LRMS=288 (M+1)

[0354] Step 2: N-(2-Amino-phenyl)-3-(4-styrylamino-phenyl)-acrylamide(71)

[0355] Following the procedure described in Example 42, steps 2, 4, butsubstituting 69 for 42, and acrylic acid for tert-butyl acrylate thetitle compound 71 was obtained in an overall yield of 60%. ¹H NMR:(DMSO-d₆) δ(ppm): 9.22 (bs, 1H), 7.45 (d, J=6.9 Hz, 2H), 7.39 (d, J=9.0Hz, 2H), 7.34 (d, J=7.4 Hz, 2H), 7.26 (dt, J=7.4 Hz, 6.8 Hz, 2H), 6.93(dt, J=7.9 Hz, 7.1 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.69 (d, J=8.5 Hz,2H), 6.63-6.55 (m, 4H), 6.44-6.37 (m, 1H), 4.95 (bs, 2H), 3.95 (bs, 2H).

Example 49 N-(2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-acrylamide(compound 72)

[0356] Step 1: N-(4-Iodo-phenyl)-4methoxy-benzamide (compound 70)

[0357] Following the procedure described in Example 47, step 2, butsubstituting 68 for 63, the title compound 70 was obtained in 90% yield.LRMS=354.0 (M+1)

[0358] Step 2: N-(2-Amino-phenyl)-3-[4-(4-methoxy-benzamide)]-acrylamide(compound 72)

[0359] Following the procedure described in Example 42, steps 2, 4, butsubstituting 70 for 42, and acrylic acid for tert-butyl acrylate thetitle compound 72 was obtained in an overall yield of 90%. ¹H NMR:(DMSO-d₆) δ(ppm): 9.4 (bs, 1H), 7.60(d, J=8.5 Hz, 1H), 7.54-7.45 (m,3H), 7.87 (d, J=7.7 Hz, 1H), 7.10 (d, J=8.8 Hz, 1H), 6.95-6.77 (m, 3H),6.62 (d, J=7.7 Hz, 2H), 6.08-6.04 (m, 2H), 4.98 (bs, 2H), 3.72 (s, 3H).

Example 50N-(2-aminophenyl)-3-}6-[2-(4-oxo-4H-quinazolin-3-yl)-ethylamino]-pyridin-3-yl}-acrylamide(compound 76)

[0360] Step 1: N-(5-Bromo-pyridin-2-yl)-ethane-1,2-diamine (compound 73)

[0361] Following the procedure described in Example 40, step 1, butusing 1,2-diaminoethane as alkyl amine, the title compound 73 wasobtained in 84% yield. ¹³C NMR (300 MHz, CD₃OD): 159.1, 148.7, 140.7,111.7, 107.2, 44.3, 41.7. LRMS=218.1 (M+1)

[0362] Step 2:3-[2-(5-Bromo-pyridin-2-ylamino)-ethyl]-3H-quinazolin-4-one (compound75)

[0363] A suspension of primary amine 73 (1.17 g, 5.40 mmol) and isatoicanhydride 74 (880 mg, 5.40 mmol) in methanol (25 mL) was stirred for 3 hat 50° C. and then concentrated. The resulting oily residue wasdissolved in 88% formic acid (20 mL) and refluxed overnight. Afterremoval of formic acid, the solid residue was purified through columnchromatography on silica gel (5% methanol in dichloromethane) to give1.24 g (3.6 mmol, 67% yield) of 75. ¹³C NMR (300 MHz, CDCl₃): 161.6,156.8, 147.7, 147.6, 147.2, 139.8, 134.5, 127.4, 126.8, 126.3, 121.6,110.1, 107.0, 46.3, 40.1. LRMS=347.1 (M+1). Step 3:N-(2-aminophenyl)-3-{6-[2-(4-oxo-4H-quinazolin-3-yl)-ethylamino]-pyridin-3-yl}-acrylamide(compound 76)

[0364] Following the procedure described in Example 42, steps 2 to 4,but substituting 75 for 42, the title compound 76 was obtained in anoverall yield of 68%. ¹H-NMR (DMSO-d6), δ(ppm): 9.24 (bs, 1H), 8.17 (dd,J=8.0 Hz, 1.6 Hz, 1H), 8.11 (bs, 1H), 8.08 (d, J=1.9 Hz, 1H), 7.82 (dt,J=8.5 Hz, 1.4 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.25 (t, J=5.8 Hz, 1H),6.90 (dt, J=15.7 Hz, 1H), 6.74 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.58 (m, 3H),4.95 (bs, 2H), 4.17 (t, J=5.2 Hz, 2H), 3.68 (m, J=5.2 Hz, 2H).

Example 51N-(2-aminophenyl)-3-{6-[2-(4-benzyl-2,6-dioxo-piperazin-1-yl)-ethylamino]-pyridin-3-yl}-acrylamide(compound 78)

[0365] Step 2:4-Benzyl-1-[2-(5-bromo-pyridin-2-ylamino)-ethyl]-piperazine-2,6-dione(compound 77)

[0366] A suspension of benzyliminodiacetic acid (702 mg, 3.15 mmol) andacetic anhydride (15 mL) was stirred at 120° C. for 45 min. The reactionmixture was diluted with dry toluene and concentrated in vacuo to removethe volatiles. The residue was dissolved in dry toluene (15 mL) andtransferred via cannula to a reaction flask containing the amine 73 (475mg, 3.2 mmol). The mixture was heated at 90° C. for 16 h, concentratedand chromatographed by column on silica gel (elution 5% methanol indichloromethane) to give 684 mg (1.70 mmol, 54% yield) of 77.

[0367] Step 3:N-(2-aminophenyl)-3-{6-[2-(4benzyl-2.6-dioxo-piperazin-1-yl)-ethylamino]-pyridin-3-yl}-acrylamide(compound 78)

[0368] Following the procedure described in Example 42, steps 2 to 4,but substituting 77 for 42, the title compound 78 was obtained in anoverall yield of 60%. ¹H-NMR (CD₃OD-d4), δ(ppm): 8.09 (d, J=1.8 Hz, 1H),7.68 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.53 (d, J=15.6 Hz, 1H), 7.29 (m, 6H),7.20 (dd, J=7.8 Hz, 1.2 Hz, 1H), 7.02 (dt, J=9.0 Hz, 1.2 Hz, 1H), 6.86(dd, J=8.1 Hz, 1.2 Hz, 1H), 6.73 (dt, J=7.5 Hz, 1.5 Hz, 1H), 6.61 (d,J=15.6 Hz, 1H), 6.50 (d, J=8.7 Hz, 1H), 4.85 (bs, 3H), 3.97 (t, J=7.5Hz, 2H), 3.60 (s, 2H), 3.57 (t, J=7.5 Hz, 2H), 3.38 (s, 4H).

Example 52(E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-cinnamide(compound 83)

[0369] Step 1: 4,6-Dichloro-2-(2-indanyl-amino)-[1,3,5]triazine(compound 79)

[0370] To a stirred solution at −78° C. of cyanuric chloride (13.15 g,71.33 mmol) in anhydrous THF (100 mL) under nitrogen was slowlycanulated a solution of 2-aminoindan (10.00 g, 75.08 mmol), i-Pr₂NEt(14.39 mL, 82.59 mmol) in anhydrous THF (60 mL). After 50 min, thereaction mixture was poured into a saturated aqueous solution of NH₄Cl,and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (AcOEt/CH₂Cl₂: 2/98→5/95) and byco-precipitation (AcOEt/hexanes) to afford the title compound 79 (18.51g, 65.78 mmol, 92% yield) as a beige powder. ¹H NMR (300 MHz, CDCl₃)δ(ppm): 7.29-7.18 (m, 4H), 6.02 (bd, J=6.3 Hz, 1H), 4.94-4.84 (m, 1H),3.41 (dd, J=16.2, 6.9 Hz, 2H), 2.89 (dd, J=16.1, 4.5 Hz, 2H).

[0371] Step 2:2-(4-Bromo-benzyl-amino)-4-chloro-6-(2-indanyl-amino)-[1,3,5]triazine(compound 80)

[0372] To a stirred solution at room temperature of 79 (2.68 g, 9.52mmol) in anhydrous THF (50 mL) under nitrogen were added i-Pr₂NEt (4.79mL, 27.53 mmol) and 4-bromobenzylamine.HCl (2.45 g, 11.01 mmol),respectively. After 17 h, the reaction mixture was poured into asaturated aqueous solution of NH₄Cl, and diluted with AcOEt. Afterseparation, the organic layer was successively washed with sat. NH₄Cl,H₂O and brine, dried over anhydrous MgSO₄, filtered and concentrated.The crude residue was then purified by flash chromatography on silicagel (AcOEt/CH₂Cl₂: 3/97→5/95) to afford the title compound 80 (4.00 g,9.29 mmol, 97% yield) as a white powder. ¹H NMR (300 MHz, CDCl₃) δ(ppm):mixture of rotamers, 7.52-7.42 (m, 2H), 7.26-7.11 (m, 6H), 6.51 and 6.12(2 m, 1H), 5.72-5.46 (m, 1H), 4.94-4.64 (m, 1H), 4.62-4.46 (m, 2H),3.43-3.16 (m, 2H), 2.92-2.74 (m, 2H).

[0373] Step 3:4-Amino-2-(4-bromo-benzyl-amino)-6-(2-indanyl-amino)-[1,3,5]triazine(compound 81)

[0374] In a 75 mL sealed flask, a solution of 80 (2.05 g, 4.76 mmol) inanhydrous 1,4-dioxane (60 mL) was stirred at room temperature, saturatedwith NH₃ gas for 5 min, and warmed to 140° C. for 18 h. The reactionmixture was allowed to cool to room temperature, the saturation stepwith NH₃ gas was repeated for 5 min, and the reaction mixture was warmedto 140° C. again for 24 h. Then, the reaction mixture was allowed tocool to room temperature, poured into 1N HCl, and diluted with AcOEt.After separation, the organic layer was successively washed with at.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 5/95) to afford the titlecompound 81 (1.96 g, 4.76 mmol, quantitative yield) as a colorless foam.¹H NMR (300 MHz, CDCl₃) δ(ppm): 7.43 (d, J=8.2 Hz, 2H), 7.25-7.12 (m,6H), 5.70-5.10 (m, 2H), 5.00-4.65 (m, 3H), 4.52 (bs, 2H), 3.40-3.10 (m,2H), 2.90-2.65 (m, 2H).

[0375] Step 4:(E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-[2-(N-t-butoxycarbonyl)-amino-phenyl]-cinamide(compound 82)

[0376] Preparation of N-[2-(N-t-Butoxycarbonyl)-amino-phenyl]-acrylamide

[0377] Following the procedure described in Example 45, step 2, butsubstituting the nitro-compound 2-(N-t-butoxycarbonyl)-amino-aniline for2-nitroaniline, the title compound was obtained in 77% yield. ¹H NMR(300 MHz, CDCl₃) δ(ppm): 8.51 (bs, 1H), 7.60-7.45 (m, 1H), 7.38-7.28 (m,1H), 7.20-7.05 (m, 2H), 6.98 (bs, 1H), 6.41 (dd, J=17.0 Hz, 1.1 Hz, 1H),6.25 (dd, J=16.9 Hz, 10.0 Hz, 1H), 5.76 (dd, J=10.2 Hz, 1.4 Hz, 1H),1.52 (s, 9H).

[0378] In a 50 mL sealed flask, a solution of 81 (300 mg, 0.73 mmol),the acrylamide (230 mg, 0.88 mmol), Et₃N (407 μl, 2.92 mmol),tri-o-tolylphosphine (POT, 13 mg, 0.04 mmol), Pd₂(dba)₃ (20 mg, 0.02mmol) in anhydrous DMF (10 mL) was stirred at room temperature,saturated with N₂ gas for 15 min, and warmed to 100° C. for 15 h. Then,the reaction mixture was allowed to cool to room temperature, pouredinto a saturated aqueous solution of NH₄Cl, and diluted with AcOEt.After separation, the organic layer was successively washed with sat.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 2/98→5/95) to afford thetitle compound 82 (240 mg, 0.41 mmol, 56% yield) as a beige solid. ¹HNMR (300 MHz, CDCl₃) δ(ppm): 8.46 (bs, 1H), 7.71 (bd, J=15.7 Hz, 1H),7.62-7.05 (m, 13H), 6.54 (bd, J=15.9 Hz, 1H), 5.95-4.90 (m, 4H),4.85-4.48 (m 3H), 3.40-3.14 (m, 2H), 2.90-2.70 (m, 2H), 1.52 (s, 9H).

[0379] Step 5:(E)-4-{[4-Amino-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino]-methyl}-N-(2-amino-phenyl)-cinnamide(compound 83)

[0380] To a stirred solution at room temperature of 82 (230 mg, 0.39mmol) in CH₂Cl₂ (5 mL) was added TFA (1 mL, 95% in water). After 18 h,the reaction mixture was poured into a saturated aqueous solution ofNaHCO₃, and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NaHCO₃, H₂O and brine, dried overanhydrous MgSO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (MeOH/CH₂Cl₂: 5/95) toafford the title compound 83 (170 mg, 0.35 mmol, 89% yield) as a yellowsolid. ¹H NMR (300 MHz, acetone-d₆) δ(ppm): 8.87 (bs, 1H), 7.69 (d,J=15.7 Hz, 1H), 7.59 (bd, J=7.7 Hz, 2H), 7.49-7.34 (m, 3H), 7.28-7.11(m, 4H), 7.05-6.91 (m, 2H), 6.88 (dd, J=8.0, 1.4 Hz, 1H), 6.69 (td,J=7.6, 1.4 Hz, 1H), 6.65-5.50 (m, 4H), 4.83-4.53 (m, 5H), 3.34-3.11 (m,2H), 2.98-2.80 (m, 2H).

Example 53N-(2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide(compound 87)

[0381] Step 1: 2,6-ditrifluoromethanesulfonyloxy-quinoline (compound 85)

[0382] A solution of 2,6-dihydroxyquinoline 84 (1.254 g, 7.78 mmol) andDMAP (a few crystals) in dry pyridine (15 mL) was treated with neattrifluoromethanesulfonic anhydride (5.2 g, 18,4 mmol, 1.2 equiv.) andstirred at 0° C. for 5 h. This solution was then poured on a mixturebrine/sat NaHCO₃ and extracted with dichloromethane (2×150 mL), dried(MgSO₄), filtered and concentrated. Purification by columnchromatography on silica gel (30% to 50% ether in hexanes) gave 2.58 g(6.1 mmol, 78% yield) of 85. ¹³C NMR (300 MHz, CDCl₃): 154.5, 147.8,144.6, 142.0, 131.6, 127.8, 124.9, 119.3, 118.7, 114.9. LRMS=426.0(M+1).

[0383] Step 2:N-(2-aminophenyl)-2-(4-methoxy-benzylamino)-quinolin-6-yl-amide(compound 87)

[0384] Following the procedure described in Example 40, steps 1, 2, butsubstituting 85 for 40, the title compound 87 was obtained in 92% yield.¹H-NMR (DMSO-d6), δ(ppm): 9.66 (bs, 1H), 8.32 (s, 1H), 8.05 (d, J=8.8Hz, 1H), 7.96 (dd, J=9.1 Hz, 2.2 Hz, 1H), 7.72 (d, J=2.2 Hz, 1H), 7.55(dd, J=8.5 Hz, 2.2 Hz, 1H), 7.34 (dd, J=8.5 Hz, 2.2 Hz, 1H), 7.20 (d,J=7.7 Hz, 1H), 6.97 (t, J=7.7 Hz, 1H), 6.90 (m 2H), 6.80 (d, J=7.9 Hz,1H), 6.61 (t, J=6.3 Hz, 1H), 4.90 (bs 2H, 4.58 (d, J=3.3 Hz, 2H), 3.73(s, 3H), 3.33 (bs, 1H).

Example 54N-(2-aminophenyl)-3-[2-(4-methoxy-benzylamino)-quinolin-6-yl]-acrylamide(compound 88)

[0385] Step 3:N-(2-aminophenyl)-3-[2-(4-methoxy-benzylamino)-guinolin-6-yl]-acrylamide(compound 88)

[0386] Following the procedure described in Example 42, steps 1 to 4,but substituting 85 for 40, the title compound 88 was obtained in anoverall yield of 71%. ¹H-NMR (DMSO-d6), δ(ppm): 9.70 (bs, 1H), 9.40 (bs,1H), 8.20 (d, J=8.9 Hz, 1H), 8.03 (bs, 2H), 7.94 (d, J=7.2 Hz, 1H), 7.64(dd, J=15.7 Hz, 2.5 Hz, 1H), 7.41 (d, J=8.5 Hz, 2H), 7.39 (m, 1H), 7.14(d, J=8.9 Hz, 1H), 7.05 (d, J=15.7 Hz, 1H), 6.97 (m, 1H), 6.95 (d, J=8.5Hz, 2H), 6.81 (d, J=8.0 Hz, 1H), 6.65 (t, J=7.2 Hz, 1H), 4.76 (s, 2H),3.75 (s, 3H).

Examples 55-84

[0387] Examples 55 to 84 describe the preparation of compounds 89 to 118using the same procedures as described for compounds 44 to 88 inExamples 40 to 54. Characterization data are presented in Tables 3a-d.TABLE 3a Characterization of Compounds Prepared in Examples 42-84

Ex. Cpd. W Y Z R Name Characterization Schm 42  50

N CH H N-(2-aminophenyl)-3-[6- (2-phenylamino- ethylamino)-pyridin-3-yl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.25 (bs, 1H), 8.21 (d, J=1.6Hz, 1H), 7.67 (d, J=8.5 Hz, 1H), 7.43 (d, J=15.7 Hz, 1H), # 7.32(d,J=7.4 Hz, 1H), 7.24 (t, J=1.0 Hz, 1H), 7.08 (t, J=7.4Hz, 2H), 6.91 (t,J=8.0 Hz, 1H), 6.75 (dt, J=8.0 Hz, 0.4 Hz, 1H), 6.57 (m, 6H), 5.20 (bs,1H), 3.48 (t, J=6.3 Hz, 2H), 3.33 (bs, 2H), 3.21 (t, J=6.3 Hz, 2H) 3 44 55b

CH CH H {4-[2-(2-amino-phenyl- carbamoyl)-vinyl]- phenyl}-carbamic acidpyridin-3-yl methyl ester ¹H NMR: (DMSO-d6) δ (ppm): 10.03 (s, 1H), 9.32(s, 1H), 8.65 (s, 1H), 8.55 (d, J=3.3 Hz, 1H), 7.85 (d, J=7.69 Hz, #1H), 7.40-7.60 (m, 6H), 7.31 (d, J=7.69 Hz, 1H), 6.89 (dd, J=7.14 Hz,J=7Hz, 1H), 6.71-6.79 (m, 2H), 6.55 (dd, J=7.1 Hz, J=7 Hz, 1H), 5.20 (s,2H), 4.93 (bs, 2H). 4 45  59

CH CH H N-(2-aminophenyl)-3- {4-[(3,4,5-trimethoxy-benzylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (CDCl₃), δ (ppm): 8.25(bs, 1H), 7.59 (d, J=15.6 Hz, 1H), 7.38 (d, J=7.5 Hz, 2H), 7.29 (d, #J=7.5 Hz, 2H), 7.25 (m, 1H), 7.02 (t, J=6.8 Hz, 1H), 6.75 (m, 2H), 6.62(d, J=15.6 Hz, 1H), 6.58 (s, 2H), 3.97 (bs, 3H), 3.80 (s, 9H), 3.78 (s,2H), 3.72 (s, 2H). 5 46  61b

N CH Me N-(2-aminophenyl)-3-[6- (4-methoxy- benzylamino)-pyridin-3-yl]-2-methyl-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.15 (bs, 1H), 8.13(bs, 1H), 7.58 (d, J=1.9 Hz, 1H), 7.30 (m, 4H), 7.12 (d, J=7.7 Hz, 1H),# 6.91 (m, 3H), 6.75 (d, J=7.8 Hz, 1H), 6.57 (m, 2H), 4.83 (bs, 2H),4.43 (d, J=5.5 Hz, 2H), 3.72 (s, 3H), 3.33 (s, 3H). 3 47  65

CH CH H N-(2-amino-phenyl)-3- [4-(4-methoxy- benzylamino)-phenyl]-acrylamide ¹H NMR: (DMSO-d6) δ (ppm): 9.15 (s, 1H), 7.24-7.38 (m, 6H),6.84-6.90 (m, 3H), 6.72 (m, 2H), 6.49-6.60 (m, 4H), 4.84 (s, 2H), 4.22(d, J=5.77 Hz, 2H). 6 48  71

CH CH H N-(2-Amino-phenyl)-3- (4-styrylamino-phenyl)- acrylamide ¹H NMR:(DMSO-d₆) δ (ppm): 9.22 (bs, 1H), 7.45 (d, J=6.9 Hz, 2H), 7.39 (d, J=9.0Hz, 2H), 7.34 (d, J=7.4 Hz, 2H), 7.26 (dt, J=7.4 Hz, 6.8 Hz, 2H), 6.93(dt, J=7.9 # Hz, 7.1 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.69 (d, J=8.5 Hz,2H), 6.63-6.55 (m, 4H), 6.44-6.37 (m, 1H), 4.95 (bs, 2H), 3.95 (bs, 2H).7 49  72

CH CH H N-{4-[2-(2-Amino- phenylcarbamoyl)-vinyl]- phenyl}-4-methoxy-benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.4 (bs, 1H), 7.60(d, J=8.5 Hz,1H), 7.54-7.45 (m, 3H), 7.87 (d, J=7.7 Hz, 1H), 7.10 (d, J=8.8 # Hz,1H), 6.95-6.77 (m, 3H), 6.62 (d, J=7.7 Hz, 2H), 6.08-6.04 (m, 2H), 4.98(bs, 2H), 3.72 (s, 3H). 7 50  76

N CH H N-(2-aminophenyl)-3- {6-[2-(4-oxo-4H- quinazolin-3-yl)-ethylamino]-pyridin-3- yl}-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.24(bs, 1H), 8.17 (dd, J=8.0 Hz, 1.6 Hz, 1H), 8.11 (bs, 1H), 8.08 (d, J=1.9Hz, 1H), # 7.82 (dt, J=8.5 Hz, 1.4 Hz, 1H), 7.64 (d, J=8.2 Hz, 2H), 7.25(t, J=5.8 Hz, 1H), 6.90 (dt, J=15.7 Hz, 1H), 6.74 (dd, J=8.0 Hz, 1.4 Hz,1H), 6.58 (m, 3H), 4.95 (bs, 2H), 4.17 (t, J=5.2 Hz, 2H), 3.68 (m, J=5.2Hz, 2H). 8 51  78

N CH H N-(2-aminophenyl)-3- {6-[2-(4-benzyl-2,6- dioxo-piperazin-1-yl)-ethylamino]-pyridin-3- yl}-acrylamide ¹H-NMR (CD₃OD-d4), δ (ppm): 8.09(d, J=1.8 Hz, 1H), 7.68 (dd, J=8.7 Hz, 2.1 Hz, 1H), 7.53 (d, J=15.6 Hz,# 1H), 7.29 (m, 6H), 7.20 (dd, J=7.8 Hz, 1.2 Hz, 1H), 7.02 (dt, J=9.0Hz, 1.2 Hz, 1H), 6.86 (dd, J=8.1 Hz, 1.2 Hz, 1H), 6.73 (dt, J=7.5 Hz,1.5 Hz, 1H), 6.61 (d, J=15.6 Hz, 1H), 6.50 (d, J=8.7 Hz, 1H), 4.85 (bs,3H), 3.97 (t, J=7.5 Hz, 2H), 3.60 (s, 2H), # 3.57 (t, J=7.5 Hz, 2H),3.38 (s, 4H). 8 52  83

CH CH H (E)-4-{[4-Amino-6-(2- indanyl-amino)- [1,3,5]triazin-2-ylamino]-methyl}-N-(2-amino- phenyl)-cinamide ¹H NMR (300 MHz, acetone-d₆) δ(ppm): 8.87 (bs, 1H), 7.69 (d, J=15.7 Hz, 1H), 7.59 (bd, J=7.7 Hz, 2H),7.49-7.34 # (m, 3H), 7.28-7.11 (m, 4H), 7.05-6.91 (m, 2H), 6.88 (dd,J=8.0, 1.4 Hz, 1H), 6.69 (td, J=7.6, 1.4 Hz, 1H), 6.65-5.50 (m, 4H),4.83-4.53 (m, 5H), 3.34-3.11 (m, 2H), 2.98-2.80 (m, 2H). 9 55  89

N CH H N-(2-aminophenyl)-3-[6- (4-methoxy- benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR (DMS0-d6), δ (ppm): 9.24 (bs, 1H), 8.19 (d, J=1.6Hz, 1H), 7.64 (d, J=8.5 Hz, 1H), 7.52 (t, J=5.5 Hz, 1H), 7.42 (d, J=15.7Hz, 1H), 7.32 (d, J=7.4 Hz, # 1H), 7.26 (d, J=8.5 Hz, 2H), 6.90 (m, 1H),6.88 (dd, J=8.5 Hz, 2H), 6.74 (d, J=6.9 Hz, 1H), 6.58 (m, 3H), 4.92 (bs,2H), 4.45 (d, J=5.5 Hz, 2H), 3.72 (s, 3H). 3 56  90

N CH H N-(2-aminophenyl)-3-{6- [(pyridin-3-ylmethyl)- amino]-pyridin-3-yl}-acrylamide ¹H-NMR (CD₃OD-d4), δ (ppm): 8.47 (bs, 1H), 8.33 (bs, 1H),8.02 (m, 1H), 7.73 (m, 1H), 7.61 (d, J=8.5 Hz, 1H), 7.46 (d, J=15.4 Hz,1H), # 7.29 (m, 1H), 7.14 (d, J=7.7 Hz, 1H), 6.94 (d, J=7.4 Hz, 1H),6.80 (d, J=7.9 Hz, 1H), 6.66 (t, J=7.9 Hz, 1H), 6.53 (m, 2H), 4.54 (m,2H), 3.59 (bs, 2H). 3 57  91

N CH H N-(2-aminophenyl)-3-{6- [(pyridin-4-ylmethyl)-amino]-pyridin-3-yl}- acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.27 (bs,1H), 8.48 (dd, J=1.6 Hz, 4.4, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.70 (m, 2H),7.42 (d, J=15.6 Hz, 1H), 7.31 # (m 3H), 6.90 (t, J=6.9 Hz, 1H), 6.73 (d,J=6.9 Hz, 1H), 6.58 (m, 4H), 4.98 (bs, 2H), 4.57 (d, J=6.0 Hz, 2H). 3 58 92

N CH H N-(2-aminophenyl)-3-[6- (4-fluoro-benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.24 (bs, 1H), 8.18(d, J=1.6 Hz, 1H), 7.65 (dd, J=8.8 Hz, 0.8 Hz, 1H), 7.60 (t, J=5.8 Hz,1H), 7.42 (d, J=15.7 Hz, 1H), 7.36 (m, # 3H), 7.13 (t, J=8.8 Hz, 2H),6.90 (t, J=7.4 Hz, 1H), 6.73 (dd, J=6.9 Hz, 1.0 Hz, 1H), 6.58 (m, 3H),4.91 (bs, 2H), 4.50 (d, J=6.0 Hz, 2H). 3 59  93

N CH H N-(2-aminophenyl)-3-(6- benzylamino-pyridin-3- yl)-acrylamide¹H-NMR (DMSO-d6), δ (ppm): 9.24 (bs, 1H), 8.17 (d, J=1.9 Hz, 1H), 7.65(dd, J=8.8 Hz, 1.6 Hz, 1H), 7.60 (t, J=6.0 Hz, 1H), 7.41 (d, J=15.7 Hz,1H), 7.31 (m, 5H), # 7.23 (m, 1H), 6.89 (dt, J=8.0 Hz, 1.6 Hz, 1H), 6.73(dd, J=8.0 Hz, 1.5 Hz, 1H), 6.58 (m, 3H), 4.92 (bs, 2H), 4.53 (d, J=6.0Hz, 2H) 3 60  94

N CH H N-(2-aminophenyl)-3-[6- (3-phenyl-propylamino)-pyridin-3-yl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.22 (bs, 1H), 8.18(ds, 1H), 7.63 (d, J=8.8 Hz, 1H), 7.42 (d, J=15.4 Hz, 1H), 7.22 (m 7H),6.90 (t, J=7.7 Hz, 1H), 6.75 # (d, J=8.0 Hz, 1H), 6.57 (m 3H), 4.92 (bs,2H), 3.29 (dt, J=7.7 Hz, 6.0 Hz, 2H), 2.66 (t, J=7.7 Hz, 2H), 1.84 (m,J=7.7 Hz, 2H). 3 61  95

N CH H N-(2-aminophenyl)-3-{6- [2-(4-methoxy-phenyl)-ethylamino]-pyridin-3- yl}-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.22(bs, 1H), 8.19 (bs, 1H), 7.62 (d, J=8.5 Hz, 1H), 7.42 (d, J=15.7 Hz,1H), 7.32 (d, J=7.8 Hz, 1H), 7.16 # (d, J=7.8 Hz, 2H), 7.13 (m, 1H),6.91 (m, 1H), 6.85 (d, J=7.9 Hz, 1H), 6.74 (d, J=7.8 Hz, 1H), 6.57 (m3H), 4.92 (bs, 2H), 3.71 (s, 3H), 3.47 (dd, J=7.3 Hz, 6.0 Hz, 2H), 2.78(t, J=7.3 Hz, 2H). 3 62  96

N CH H N-(2-aminophenyl)-3-[6- (4-dimethylamino- benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.23 (bs, 1H), 8.18 (bs, 1H),7.63 (d, J=8.2 Hz, 1H), 7.41 (m, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.15 (d,J=8.5 Hz, 2H), 6.90 # (t, J=7.4 Hz, 1H), 6.74 (d, J=7.0 Hz, 1H), 6.68(d, J=8.5 Hz, 2H), 6.58 (m, 3H), 4.91 (bs, 2H), 4.39 (d, J=5.5 Hz, 2H),(bs, 2H). 3 63  97

N CH H N-(2-aminophenyl)-3-[6- (3-imidazol-1-yl- propylamino)-pyridin-3-yl]-acrylamide ¹H-NMR (CD₃OD-d4), δ (ppm): 8.09 (bs, 1H), 8.05 (d, J=1.9Hz, 1H), 7.67 (m, 2H), 7.49 (d, J=15.7 Hz, 1H), 7.28 (m, 2H), 7.17 (m,2H), 6.98 (dt, J=13.7 # Hz, 7.7 Hz, 1H), 6.83 (dd, J=8.0 Hz, 1.1 Hz,1H), 6.69 (dt, J=9.1 Hz, 1.4 Hz, 1H), 6.58 (d, J=15.7 Hz, 1H), 6.51 (d,J=8.8 Hz, 1H), 4.15 (t, J=7.1 Hz, 2H), 3.29 (m, 2H), 2.08 (m, J=6.9 Hz,2H). 3 64  98

N CH H N-(2-aminophenyl)-3-[6- (3-trifluoromethoxy-benzylamino)-pyridin-3- yl]-acrylamide ¹H-NMR (acetone-d6), δ (ppm):8.75 (bs, 1H), 8.23 (d, J=1.9 Hz, 1H), 7.69 (d, J=8.2 Hz, 1H), 7.55 (d,J=15.4 Hz, 1H), 7.43 (m, 2H), 7.34 (bs, 2H), 7.19 (d, # J=6.6 Hz, 1H),6.93 (m, 2H), 6.83 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.67 (m, 3H), 4.71 (d,J=6.3 Hz, 2H), 4.65 (bs, 2H). 3 65  99

N CH H N-(2-aminophenyl)-3-[6- (4-trifluoromethoxy-benzylamino)-pyridin-3- yl]-acrylamide ¹H-NMR (acetone-d6), δ (ppm):8.81 (bs, 1H), 8.21 (d, J=1.9 Hz, 1H), 7.66 (d, J=7.4 Hz, 1H), 7.56 (d,J=15.7 Hz, 2H), 7.49 (d, 2H), J=8.2 Hz, 1H), 7.34 (d, # J=8.1 Hz, 1H),7.25 (t, J=8.0 Hz, 1H), 6.93 (m, 2H), 6.73 (m, 3H), 4.67 (d, J=6.0 Hz,2H), 4.66 (bs, 2H). 3 66 100

N CH H N-(2-aminophenyl)-3-[6- (3,5-difluoro- benzylamino)-pyridin-3-yl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.25 (bs, 1H), 8.18 (d, J=2.2Hz, 1H), 7.67 (m, 2H), 7.42 (d, J=15.7 Hz, 1H), 7.31 (d, J=7.7 Hz, 1H),7.08 (dt, J=9.3 Hz, 2.2 Hz, 1H), # 7.03 (dd, J=8.8 Hz, 1.9 Hz, 2H), 6.90(dt, J=7.3 Hz, 1.4 Hz, 1H), 6.73 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.60 (m3H), 4.92 (bs, 2H), 4.56 (d, J=6.0 Hz, 2H). 67 101

N CH H N-(2-aminophenyl)-3-[6- (3-trifluoromethyl-benzylamino)-pyridin-3- yl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.25(bs, 1H), 8.14 (bs, 1H), 7.86 (m, 6H), 7.42 (d, J=15.6 Hz, 1H), 7.31 (d,J=7.4 Hz, 1H), 6.90 (dt, J=8.8 Hz, 1.1 Hz, 1H), 6.74 (dd, # J=8.0 Hz,1.4 Hz, 1H), 6.60 (m 3H), 4.96 (bs, 2H), 4.63 (d, J=5.8 Hz, 2H). 68 102

N CH H 3-[6-(3-aminomethyl- benzylamino)-pyridin-3-yl]-N-(2-aminophenyl)- acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.28 (bs,1H), 8.17 (bs, 1H), 7.66 (d, J=5.8 Hz, 2H), 7.37 (m, 6H), 6.88 (dd,J=8.0 Hz, 0.9 Hz, 1H), 6.73 (dd, J=8.0 Hz, 0.9 Hz, 1H), # 6.59 (m, 3H),4.55 (d, J=5.8 Hz, 2H), 3.96 (s, 2H), 3.37 (bs, 4H). 70 104

CH CH H {4-[2-(2-amino-phenyl- carbamoyl)-vinyl]- benzyl}-carbamic acidpyridin-3-yl methyl ester ¹H NMR: (DMSO-d6) δ (ppm): 9.36 (s, 1H), 8.57(s, 1H), 8.51 (d, J=4.6 Hz, 1H), 7.91 (m, 1H), 7.77 (d, J=7.68 Hz, 1H),7.28-7.57 (m, 7H), 6.88 # (dd, J=15.66 Hz, 4.40 Hz, 2H), 6.73 (m, 1H),6.56 (m, 1H), 5.01 (s, 2H), 4.93 (bs, 2H), 4.10 (d, J=6.04 Hz, 2H). 71105

CH CH H (2-{4-[2-(2-amino- phenylcarbamoyl)-vinyl]-phenyl}-ethyl)-carbamic acid pyridin-3-yl methyl ester ¹H NMR: (DMSO-d6)δ (ppm): 9.34 (s, 1H), 8.52 (m, 2H), 7.71 (d, J=7.69 Hz, 1H), 7.20-7.60(m, 8H), 6.87 (m, 2H), 6.73 (m, 1H), 6.56 # (m, 1H), 5.03 (s, 2H), 4.92(s, 2H), 3.30 (m, 2H), 2.75 (m, 2H). 4 72 106

CH CH H N-(2-aminophenyl)-3-{4- [(3,4,5-trimethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (acetone-d6), δ (ppm):8.49 (bs, 1H), 8.41 (d, J=7 Hz, 1H), 7.63 (d, J=15.6 Hz, 1H), 7.56 (d,J=8 Hz, 2H), 7.45 # (d, J=8 Hz, 2H), 7.07 (m, 2H), 6.90 (d, J=15.6 Hz,1H), 6.76 (m, 1H), 6.74 (m, 1H), 5.99 (s, 2H), 4.36 (s, 2H), 3.69 (s,6H), 3.68 (bs, 2H), 3.67 (s, 3H). 5 73 107

CH CH H N-(2-aminophenyl)-3-(4- {[(3,4,5-trimethoxy-benzyl)-amino]-methyl}- pheyl)-acrylamide ¹H-NMR (CDCl₃), δ (ppm): 7.70(bs, 1H), 7.43 (d, J=7.4 Hz, 1H), 7.33 (d, J=4.9 Hz, 2H), 7.26 (d, J=4.9Hz, 2H), # 7.25 (m, 1H), 7.03 (t, J=7.4 Hz, 1H), 6.78 (d, J=7.4 Hz, 1H),6.75 (m, 1H), 6.61 (s, 2H), 6.57 (m, 1H), 4.08 (bs, 2H), 3.86 (s, 6H),3.83 (s, 3H), 3.50 (s, 2H), 3.47 (s, 2H), 2.21 (s, 3H). 5 74 108

CH CH H N-(2-aminophenyl)-3-{4- [(3,4,5-trimethoxy-phenyl)-amino]-methyl}- phenyl}-acrylamide ¹H-NMR (CDCl₃), δ (ppm): 7.74(d, J=15.4 Hz, 1H), 7.50 (d, J=7.4 Hz, 2H), 7.25 (m, 3H), 7.06 (t, J=1.9Hz, # 1H), 6.82 (d, J=7.4 Hz, 2H), 6.58 (d, J=15.4 Hz, 1H), 5.96 (s,2H), 4.50 (s, 2H), 3.79 (s, 6H), 3.78 (bs, 2H), 3.77 (s, 3H), 3.00 (s,3H). 5 75 109

CH CH H N-(2-Amino-phenyl)-3- {4-[(6-methoxy-pyridin-3-ylamino)-methyl]- phenyl}-acrylamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.4(bs, 1H), 7.60(d, J=8.5 Hz, 1H), 7.54-7.45 (m, # 3H), 7.87 (d, J=7.7 Hz,1H), 7.10 (d, J=8.8 Hz, 1H), 6.95-6.77 (m, 3H), 6.62 (d, J=7.7 Hz, 2H),6.08-6.04 (m, 2H), 4.98 (bs, 2H), 3.72 (s, 3H). 5 76 110

CH CH H N-(2-Amino-phenyl)-3- [4-(quinolin-2-ylsulfanyl-methyl)-phenyl]- acrylamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.41 (bs, 1H),8.21 (d, J=8.5, 1H), 7.97 (dt, J=7.7, 8.8 Hz, # 2H), 7.78 (dt, J=7.1 Hz,8.2 Hz, 1H), 7.61-7.53 (m, 5H), 7.40 (dd, J=8.5 Hz, 7.6 Hz, 2H),6.97-6.77 (m, 4H), 6.6 (dt, J=7.7 Hz, 7.5 Hz, 1H), 4.98 (bs, 2H), 4.65(bs, 2H). 5 77 111

CH CH H N-(2-amino-phenyl)-3- {4-[(pyridin-3-ylmethyl)- amino]-phenyl}-acrylamide ¹H NMR: (DMSO-d6) δ (ppm): 9.15 (s, 1H), 7.24-7.38 (m, 6H),6.84-6.90 (m, 3H), 6.72 (m, 2H), 6.49-6.60 (m, 4H), 4.84 (s, 2H), 4.22(d, J=5.77 Hz, 2H). 6 78 112

N CH H N-(2-Amino-phenyl)-3- (6-styrylamino-pyridin- 3-yl)-acrylamide ¹HNMR: (DMSO-d₆) δ (ppm): 7.96 (d, J=9.1 Hz, 2H), 7.55 (d, J=14.2 Hz, 1H),# 7.48 (d, J=7.4 Hz, 2H), 7.39-7.29 (m, 4H), 7.07-6.91 (m, 3H),6.81-6.64 (m, 3H), 6.47-6.38 (m, 1H), 4.21 (bs, 2H). 7 79 113

N N H N-(2-amino-phenyl)-3- [2-(4-nitro-benzylamino)- pyrimidin-5-yl]-acrylamide ¹H NMR: (DMSO-d6) δ (ppm): 9.30 (s, 1H), 8.58 (bs, 2H), 8.36(m, 1H), # 8.20 (m, 2H), 7.58 (m, 2H), 7.28-7.42 (m, 2H), 6.52-6.92 (m,4H), 4.90 (s, 2H), 4.64 (d, J=6 Hz, 2H). 7 80 114

N CH H N-(5-[2-(2-Amino- phenylcarbamoyl-vinyl)-pyridin-2-yl)-4-methoxy- benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 10.87 (bs,1H), 9.45 (bs, 1H), 8.66 (bs, 1H), # 8.33 (d, J=7.4 Hz, 1H), 8.14-8.08(m, 3H), 7.63 (d, J=15.6 Hz, 1H), 7.40 (d, J=7.7 Hz, 1H), 7.08 (d, J=6.8Hz, 2H), 6.97 (d, J=12.3 Hz, 2H), 6.80 (d, J=7.9 Hz, 1H), 6.63 (dt,J=7.7 Hz, 7.4Hz, 1H), 5.06 (bs, 2H), 3.88 (s, 3H) 7 81 115

N N H 3-[2-(4-amino-benzyl- amino)-pyrimidin-5-yl]- N-(2-amino-phenyl)-acrylamide ¹H NMR: (DMSO-d6) δ (ppm): 9.27 (s, 1H), 8.83 (s, 2H), 7.97(t, J=6 Hz, 1H), 7.37 # (d, J=15.9 Hz, 1H), 7.29 (d, J=7.11 Hz, 1H),6.96 (d, J=8.24 Hz, 2H), 6.88 (m, 1H), 6.70 (m, 2H), 6.55 (m, 1H), 6.47(d, J=8.2 Hz, 2H), 4.90 (s, 4H), 4.34 (d, J=6.0 Hz, 2H). 7 82 116

N CH H N-(2-aminophenyl)-3-[6- (3,4,5-trimethoxy-benzylamino)-pyridin-3- yl]-acrylamide ¹H-NMR (CDCl₃), δ (ppm): 8.38(bs, 1H), 7.49 (m, 1H), 7.42 (dd, J=8.5 Hz, 2.2 Hz, 1H), 7.41 (m, 1H),7.30 (d, # J=7.9 Hz, 1H), 7.10 (bs, 1H), 7.02 (t, J=7.4 Hz, 1H), 6.75(d, J=15.0 Hz, 1H), 6.73 (m, 1H), 6.65 (m, 2H), 6.36 (d, J=8.8 Hz, 1H),6.23 (d, J=15.0 Hz, 1H), 4.34 (s, 2H and bs, 2H), 3.84 (s, 3H), 3.81 (s,6H). 7, 3 83 117

N CH H N-(2-Amino-phenyl)-3- [6-(4-methyl- benzylamino)-pyridin-3-yl]-acrylamide ¹H NMR: (DMSO-d₆) δ (ppm): 8.28 (bs, 1H), 7.98 (d, J=9.6Hz, 1H), 7.57 (d, J=15.6 Hz, 1H), 7.38 (d, J=7.7 Hz, # 1H), 7.29 (d,J=7.9 Hz, 2H), 7.22 (d, J=7.6 Hz, 2H), 7.08 (dt, J=8.2 Hz, 7.7 Hz, 1H),6.98 (d, J=9.1 Hz, 2H), 6.87 (t, J=8.2 Hz, 1H), 6.75 (d, J=15.1 Hz, 1H),4.57 (s, 2H), 2.53 (s, 3H). 7 84 118

N N H N-(2-amino-phenyl)-3- [2(4-methoxy- benzylamino)-pyrimidin-5-yl]-acrylamide ¹H NMR: (DMSO-d6) δ (ppm): 9.27 (s, 1H), 8.54 (s, 2H),8.12 (m, 1H), 7.30 (m, 4H), 6.53-6.91 (m, 6H), 4.90 (s, 2H), # 4.46 (d,J=4.9 Hz, 2H), 3.7 (s, 3H). 7  84b 118b

N CH H N-(2-Amino-phenyl)-3- [6-(3,4-dimethoxy- phenyl)-pyridin-3-yl]-acrylamide ¹H NMR (20% CD₃OD in CDCl₃):

8.75 (s, 1H), 7.95 # (m, 1H), 7.74-7.59 (m, 3H), 7.50 (m, 1H), 7.24 (d,J=7.8 Hz, 1H), 7.07 (m, 1H), 6.95 (d, J=8.4 Hz, 1H), 6.89-6.83 (m, 3H),3.96 (s, 3H), 3.91 (s, 3H). 9, 15

[0388] TABLE 3b

Ex. Cpd. n Name Characterization Scheme 53 87 0 2-(4-methoxy- ¹H-NMR(DMSO-d6), δ (ppm): 9.66 (bs, 1H), 8.32 (s, 1H), 8.05 (d, J=8.8 Hz, 10benzylamino)-quinoline- 1H), 7.96 (dd, J=9.1 Hz, 2.2 Hz, 1H), 7.72 (d,J=2.2 Hz, 1H), 7.55 (dd, J=8.5 6-carboxylic acid (2- Hz, 2.2 Hz, 1H),7.34 (dd, J=8.5 Hz, 2.2 Hz, 1H), 7.20 (d, J=7.7 Hz, 1H), 6.97aminophenyl)-amide (t, J=7.7 Hz, 1H), 6.90 (m 2H), 6.80 (d, J=7.9 Hz,1H), 6.61 (t, J=6.3 Hz, 1H), 4.90 (bs 2H), 4.58 (d, J=3.3 Hz, 2H), 3.73(s, 3H), 3.33 (bs, 1H). 54 88 1 N-(2-aminophenyl)-3-[2- ¹H-NMR(DMSO-d6), δ (ppm): 9.70 (bs, 1H), 9.40 (bs, 1H), 8.20 (d, J=8.9 Hz, 10(4-methoxy- 1H), 8.03 (bs, 2H), 7.94 (d, J=7.2 Hz, 1H), 7.64 (dd, J=15.7Hz, 2.5 Hz, 1H), benzylamino)-quinolin-6- 7.41 (d, J=8.5 Hz, 2H), 7.39(m, 1H), 7.14 (d, J=8.9 Hz, 1H), 7.05 (d, J=15.7 yl]-acrylamide Hz, 1H),6.97 (m, 1H), 6.95 (d, J=8.5 Hz, 2H), 6.81 (d, J=8.0 Hz, 1H), 6.65 (t,J=7.2 Hz, 1H), 4.76 (s, 2H), 3.75 (s, 3H).

[0389] TABLE 3c

Ex. Cpd. Name Characterization Scheme 43 51N-(2-aminophenyl)-3-[6-(4-methoxy- ¹H-NMR (CDCl₃), δ (ppm): 7.60 (bs,1H), 7.55 (bs, 1H), 7.43 (t, J=7.7 3benzylamino)-pyridin-2-yl]-acrylamide Hz, 1H), 7.29 (d, J=8.3 Hz, 2H),7.17 (d, J=15.1 Hz, 1H), 7.06 (t, J= 7.7 Hz, 1H), 6.88 (d, J=8.3 Hz,2H), 6.80 (m, 2H), 6.70 (m, 3H), 6.41 (d, J=8.5 Hz, 1H), 4.50 (d, J=5.5Hz, 2H), 3.80 (s, 3H), 3.45 (bs, 2H).

[0390] TABLE 3d

Ex. Cpd W Y Z R Name Characterization Schm 347 492

CH CH H N-(2-Amino-phenyl)-3- {4-[(4,6-dimethoxy- pyrimidin-2-ylamino)-methyl]-phenyl}- acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.36 (bs, 1H),7.55 (d, # J=7.4 Hz, 2H), 7.48 (s, 1H), 7.38 (d, J=7.9 Hz, 2H), 7.33 (dJ=7.9 Hz, 1H), 6.91 (m, 2H), 6.73 (d, J=8.2 Hz, 1H), 6.56 (dd, J=7.4,7.7 Hz, 1H), 5.35 (s, 1H), 4.93 (bs, 2H), 4.46 (dd, J=6.04 2H), 3.32 (s,6H) 3, 7 348 493

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-chloro-6- methoxy-pyrimidin-2-ylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.37(bs, 1H), # 7.58-7.50 (m, 3H), 7.37-7.32 (m, 3H), 6.94-6.83 (m, 2H),6.75 (d J=8.0 Hz, 1H), 6.57 (t, J=7.5, 1H), 6.13 (bs, 1H), 4.94 (bs,2H), 4.48 (d, J=6.0, 2H), 3.84 (s, 3H) 3, 7 349 494

CH CH H N-(2-Amino-phenyl)-3- [4-(3,5-dimethoxy- benzylamino)-phenyl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.38 (bs, 1H), # 7.55-7.40 (m,6H), 6.88-6.57 (m, 3H), 6.35-6.32 (m, 1H), 5.73 (m, 3H), 4.94 (s, 2H),4.26 (s, 2H), 3.63 (s, 6H). 3, 7 350 495

CH CH H N-(2-Amino-phenyl)-3- [4-(3,5-dinitro- benzylamino)-phenyl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.38 (bs, 1H), 7.74 # (bs, 3H),7.61 (d, J=8.2 Hz, 2H), 7.56-7.44 (m, 3H), 7.32 (d J=8.0 Hz, 1H),6.91-6.85 (m, 2H), 6.73 (d, J=7.9 Hz, 1H), 6.66-6.56 (m, 1H), 4.93 (bs,2H), 4.52 (bs, 2H). 3, 7 351 496

CH CH H N-(2-Amino-phenyl)-3- [4-(3-trifluoromethoxy-benzylamino)-phenyl]- acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.22 (bs,1H), 7.52 # (d, J=7.9 Hz, 2H), 7.44 (bs, 1H), 7.38 (bs, 3H), 7.28 (dJ=6.9 Hz, 2H), 6.95-6.92 (m, 2H), 6.79 (d, J=8.2 Hz, 1H), 6.69-6.59 (m,3H), 4.95 (bs, 2H), 4.45 (bs, 2H). 58 352 497

CH CH H N-(2-Amino-phenyl)-3- [4-(3,4,5-trimethoxy- phenoxymethyl)-phenyl]-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.45 (bs, 1H), 8.01 # (bs,2H), 7.78-7.5 (m, 4H), 7.49-7.40 (m, 1H), 6.98 (dd, J=7.0, 8.2 Hz, 1H),6.82 (d, J=7.0 Hz, 1H), 6.64 (dd, J=7.0, 7.6 Hz, 1H), 6.41 (bs, 2H),5.17 (s, 2H), 3.81 (s, 6H), 3.64 (s, 3H). 3, 7 353 498

CH CH H N-(2-Amino-phenyl)-3- [4-(6,7-dimethoxy-3,4-dihydro-1H-isoquinolin- 2-yl)-phenyl]- acrylamide ¹H-NMR (DMSO-d6), δ(ppm): 9.22 (bs, 1H), 7.17 # (d, J=8.2 Hz, 2H), 6.97 (d, J=8.2 Hz, 2H),6.93 (d, J=7.6 Hz, 1H), 6.85 (bs, 1H), 6.77 (bs, 1H), 6.60-6.53 (m, 3H),6.43-6.40 (m, 2H), 4.97 (bs, 2H), 4.43 (bs, 2H), 3.78 (s, 3H), 3.77 (s,3H), 2.87-2.85 (m, 2H), 2.65-2.62 (m, 2H). 37 354 499

CH CH H N-(2-Amino-phenyl)-3- (4-{[(1H-indol-2- ylmethyl)-(3,4,5-trimethoxy-phenyl)- amino]-methyl}- phenyl)-acrylamide ¹H-NMR(DMSO-d6),δ (ppm): 10.77 (bs, 1H), 9.39 # (bs, 1H), 7.62 (d, J=7.9 Hz, 1H), 7.49(d, J=5.7 Hz, 2H), 7.37 (d, J=7.9 Hz, 2H), 7.26 (d, J=7.9, 2H), 7.10 (t,J=7.5 Hz, 2H), 7.00-6.83 (m, 4H), 6.78 (d, J=7.9 Hz, 1H), 6.61 (t, J=7.5Hz, 1H), 5.98 (s, 1H), 5.32 (bs, 1H), 4.98 (bs, 2H), 4.32 (d, J=5.2 Hz,2H), 3.98 (bs, 2H), 3.73 (s, 3H), 3.67 (s, 3H), 3.64 (s, 3H). 58 355 500

CH CH H N-(2-Amino-phenyl)-3- [4-(3,4,5-trimethoxy-phenylsulfanylmethyl)- phenyl]acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.69(bs, 1H), 8.04 # (d, J=8.3 Hz, 2H), 7.78 (d, J=8.3 Hz, 2H), 7.58-7.55(m, 2H), 7.06 (d, J=6.2 Hz, 1H), 6.96 (d, J=7.3 Hz, 1H), 6.90 (d, J=7.0Hz, 1H), 6.60 (bs, 1H), 5.81 (s, 2H), 4.34 (bs, 2H), 3.78 (s, 6H), 3.67(s, 3H). 3, 7 356 501

CH CH H 3-{4-[(6-Acetyl- benzo[1,3]dioxol-5- ylamino)-methyl]-phenyl}-N-(2-amino- phenyl)-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.81(bs, 1H), 7.95 # (d, J=7.9 Hz, 2H), 7.58 (d, J=7.9 Hz, 2H), 7.39 (bs,1H), 7.21 (d, J=7.4 Hz, 1H), 7.02-7.00 (m, 2H), 6.85 (d, J=7.5 Hz, 1H),6.64 (t, J=7.4 Hz, 1H), 6.60 (bs, 1H), 6.36 (bs, 1H), 6.00 (d, J=2.2 Hz,2H), 4.60 (bs, 2H), 2.50 (bs, 3H). 58 357 502

CH CH H N-(2-Amino-phenyl)-3- {4-[(5-methoxy- benzothiazol-2-ylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.43(bs, 1H), 8.37 # (bs, 1H), 7.66-7.57 (m, 3H), 7.49 (d, J=7.5 Hz, 2H),7.37-7.33 (m, 3H), 6.96-6.90 (m, 1H), 6.87 (d, J=8.8 Hz, 1H), 6.80 (d,J=7.9 Hz, 1H), 6.63 (t, J=7.5 Hz, 1H), 4.99 (bs, 2H), 4.64 (bs, 2H),3.37 (s, 3H). 58 358 503

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-morpholin-4-yl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.42(bs, 1H), 7.63-7.56 (m, 3H), # 7.47 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.5Hz, 1H), 6.95 (d, J=8.3 Hz, 1H), 6.82 (bs, 1H), 6.77 (d, J=8.4 Hz, 2H),6.66-6.56 (m, 3H), 5.91 (bs, 1H), 5.01 (bs, 2H), 4.30 (bs, 2H), 3.74(bs, 4H), 2.93 (bs, 4H). 58 359 504

CH CH H N-(2-Amino-phenyl)-3- (4-[(4-trifluoromethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.42(s, 1H), 7.64 (d, J=7.9 Hz, 2H), # 7.59 (d, J=15.9 Hz, 1H), 7.48 (d,J=8.0 Hz, 2H), 7.39 (d J=7.4 Hz, 1H), 7.10 (d, J=8.2 Hz, 2H), 6.99 (d,J=7.1 Hz, 1H), 6.92 (d, J=15.4 Hz, 1H), 6.81 (dd, J=1.3, 8.0 Hz, 1H),6.61-6.68 (m, 4H), 4.99 (s, 2H), 4.36 (d, J=6.0 Hz, 2H). 3, 33 360 505

CH CH H N-(2-Amino-phenyl)-3- [4-(benzo[1,3]dioxol-5- ylaminomethyl)-phenyl]-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.42 (s, 1H), 7.63 (d,J=7.7 Hz, 2H), 7.59 (d, J=15.4 Hz, 1H), 7.47 (d, # J=8.0 Hz, 2H), 7.40(d, J=7.7 Hz, 1H), 6.99 (d, J=7.1 Hz, 1H), 6.92 (d, J=16.2 Hz, 1H), 6.81(dd, J=1.4, 8.0 Hz, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.62 (dd, J=1.4, 7.7Hz, 1H), 6.34 (d, J=2.2 Hz, 1H), 6.05 (m, 2H), 5.87 (s, 2H), 4.99 (s,2H), 4.29 (d, J=6.0 Hz, 2H). 3, 33 361 506

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-trifluoromethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.43(s, 1H), 7.57-7.66 (m, 3H), 7.48 (d, J=7.6 Hz, 2H), 7.40 (d, # J=7.6 Hz,1H), 7.20 (dd, J=8.2, 8.2 Hz, 1H), 6.99 (d, J=7.6 Hz, 1H), 6.93 (d,J=15.2 Hz, 1H), 6.81 (m, 2H), 6.64 (m, 2H), 6.49-6.55 (m, 2H), 5.00 (s,2H), 4.38 (d, J=5.3 Hz, 2H). 3, 33 362 507

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-methoxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.42 (s, 1H), 7.63 (d,J=7.6 Hz, 2H), 7.59 (d, J=15.8 Hz, 1H), 7.47 (d, # J=7.6 Hz, 2H), 7.40(d, J=7.6 Hz, 1H), 6.90-7.02 (m, 3H), 6.81 (d, J=7.6 Hz, 1H), 6.64 (dd,J=7.0, 7.0 Hz, 1H), 6.36 (m, 1H), 6.24 (d, J=8.2 Hz, 1H), 6.18 (m, 2H),5.00 (s, 2H), 4.34 (d, J=5.3 Hz, 2H), 3.69 (s, 3H). 3, 33 363 508

CH CH H N-(2-Amino-phenyl)-3- {4-[(2-methoxy- phenylamino)-methyl]-phenyl)-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.42 (s, 1H), 7.62 (d,J=7.0 Hz, 2H), 7.58 (d, J=15.2 Hz, 1H), 7.46 (d, J=7.6 Hz, 2H), # 7.40(d, J=7.0 Hz, 1H), 6.94-7.00 (m, 1H), 6.87 (d, J=7.6 Hz, 2H), 6.81 (d,J=7.6 Hz, 1H), 6.73 (dd, J=7.6, 7.6 Hz, 1H), 6.56-6.66 (m, 2H), 6.45 (d,J=7.6 Hz, 1H), 5.68 (t, J=5.9 Hz, 1H), 4.99 (s, 2H), 4.41 (d, J=6.4 Hz,2H), 3.87 (s, 3H). 3, 33 364 509

CH CH H N-(2-Amino-phenyl)-3- (4-phenylaminomethyl- phenyl)-acrylamide¹H-NMR (DMSO-d₆), δ (ppm): 9.42 (s, 1H), 7.63 (d, J=7.9 Hz, 2H), 7.59(d, J=15.8 Hz, 1H), 7.48 (d, J=7.9 Hz, 2H), 7.39 (d, J=7.5 Hz, 1H), 7.10# (2d, J=7.5, 7.5 Hz, 2H), 6.99 (d, J=7.5 Hz, 1H), 6.92 (d, J=16.2 Hz,1H), 6.81 (d, J=7.5 Hz, 1H), 6.55-6.64 (m, 4H), 6.32 (t, J=6.0, 1H),4.99 (s, 2H), 4.35 (d, J=5.7 Hz, 2H). 3, 33 365 510

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-isopropyl- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.42 (s, 1H), 7.62 (d,J=7.0 Hz, 2H), 7.59 (d, J=15.8 Hz, 1H), 7.47 (d, # J=8.2 Hz, 2H), 7.40(d, J=7.6 Hz, 1H), 6.89-6.99 (m, 4H), 6.81 (d, J=7.6 Hz, 1H), 6.64 (dd,J=7.0, 7.6 Hz, 1H), 6.56 (d, J=8.2 Hz, 2H), 6.14 (t, J=5.9 Hz, 1H), 4.99(s, 2H), 4.32 (d, J=5.9 Hz, 2H), 2.76 (m, 1H), 1.17 (d, J=7.0 Hz, 6H).3, 33 366 511

CH CH H N-(2-Amino-phenyl)-3- [4-(biphenyl-4- ylaminomethyl)-phenyl]-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.43 (s 1H) 7.57-7.66 (m,5H), 7.40-7.52 (m, 7H), 7.27 (dd, J=7.0, 7.6 Hz, 1H), 6.98 # (d, J=7.6Hz, 1H), 6.93 (d, J=15.2 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.73 (d, J=8.2Hz, 2H), 6.64 (dd, J=7.6 Hz, 1H), 6.56 (t, J=5.9 Hz, 1H), 4.99 (s, 2H),4.12 (d, J=5.9 Hz, 2H). 3, 33 367 512

CH N H N-(2-Amino-phenyl)-3- {6-[(3,4,5-trimethoxy-phenylamino)-methyl]- pyridin-3-yl}-acrylamide ¹H-NMR (DMSO-d₆), δ(ppm): 9.50 (s, 1H), 8.81 (s, 1H), 8.05 (d, J=8.2 Hz, 1H), 7.64 (d,J=15.7 Hz, 1H), # 7.52 (d, J=8.2 Hz, 1H), 7.39 (d, J=7.4 Hz, 1H),6.96-7.05 (m, 2H), 6.81 (d, J=8.0 Hz, 1H), 6.64 (dd, J=7.4, 7.4 Hz, 1H),6.26 (m, 1H), 5.96 (s, 2H), 5.01 (s, 2H), 4.43 (d, J=5.5 Hz, 2H), 3.72(s, 6H), 3.56 (s, 3H). 3, 33 369 514

CH CH H N-(2-Amino-phenyl)-3- (4-{[1-(3-benzyl-7- chloro-4-oxo-3,4-dihydro-quinazolin-2- yl)-ethylamino]-methyl}- phenyl)-acrylamide ¹H-NMR(DMSO-d₆), δ (ppm): 9.50(s, 1H), 8.28 (d, J=8.4 Hz, 1H), 7.81-7.72 (s,3H), 7.66 (d, # J=8.1 Hz, 2H), 7.88 (d, J=15.6 Hz, 1H), 7.50 (d, J=8.1Hz, 2H), 7.45-7.26 (m, 4H), 7.24-7.15 (m, 2H), 7.00-6.86 (m, 2H), # 6.84(d, J=8.1 Hz, 1H), 6.68 (t, J=7.5 Hz, 1H), 5.45 (d, J=16.8 Hz, 1H), 533(d, J=16.8 Hz, 1H), 4.62 (bs, 1H), 4.25 (d, J=12.9 Hz, 1H), 4.92 (d,J=12.9 Hz, 1H), 1.91 (m, 2H), 1.28 (m, 1H), 0.90 (m, 1H), 0.72 (t, J=7.5Hz, 3H). 55 371 516 Br— CH CH CH N-(2-Amino-phenyl)-3- (4-bromo-phenyl)-acrylamide ¹H NMR: (Acetone-d₆) δ (ppm): 9.47 (bs, 1H), 7.72-7.56 (m,5H), 7.39 (d, J=7.4 Hz, 1H), 7.00-6.95 (m, 2H), 6.81 (d, J=6.9 Hz, 1H),6.64 (t, J=7.1 Hz, 1H), 5.00 (bs, 2H). 14 372 517

CH CH CH N-(2-Amino-phenyl)-4- (2,4,5-trimethoxy- benzylamino)-benzamide¹H NMR: (CD₃OD) δ (ppm): 7.61 (d, J=15.4 Hz, 1H), 7.44 (d, J=8.4 Hz,2H), 7.25 (d, J=7.5 Hz, 1H), 7.10 (t, # J=7.5 Hz, 1H), 7.00 (s, 1H),6.94 (d, J=8.4 Hz, 1H), 6.81 (t, J=7.0 Hz, 1H), 6.76 (s, 1H) 6.70 (d,J=8.4 Hz, 2H), 6.92 (d, J=15.4 Hz, 1H), 4.35 (s, 2H), 3.94 (s, 3H), 3.92(s, 3H), 3.77 (s, 3H). 1, 7, 10 373 518

CH CH CH 4-(2-Amino-phenyl)-3- {4-[1-(3,4,5-trimethoxy-phenylamino)-ethyl]- phenyl}-acrylamide 1H NMR (DMSO-d6) δ (ppm): 9.24(s, 1H), 8.00 1(d, J=12 Hz, 1H); 7.80 (d, J=12 Hz, 1H), # 7.40-7.70 (m,7H), 6.80-7.00 (m, 2H), 6.70 (d, J=12 Hz, 1H), 6.20 (s, 2H), 4.50 (m,1H), 3.70 (s, 6H), 3.50 (s, 3H), 1.50 (d, 3H). 58 374 519

C CH H N-(2-Amino-phenyl)-3- (9H-fluoren-2-yl)- acrylamide ¹H NMR (300MHz, DMSO-d₆) δ (ppm): 9.41 (s, 1H), 8.00 (t, J=7.9 Hz, 2H), 7.88 (s,1H), 7.77-7.56 (m, # 3H), 7.52-7.32 (m, 3H), 7.00 (d, J=15.8 Hz, 1H),6.96 (t, J=7.5 Hz, 1H), 6.80 (d, J=7.9 Hz, 1H), 6.63 (t, J=7.5 Hz, 1H),5.00 (s, 2H), 4.03 (s, 2H). 59 375 520

CH CH H N-(2-Amino-phenyl)-4- [2-(2-amino- phenylcarbamoyl)-vinyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.71 (s, 1H), 9.43(s, 1H), AB system (δ_(A)=8.05, δ_(B)=7.75, # J=7.9 Hz, 4H), 7.62 (d,J=15.8 Hz, 1H), 7.36 (d, J=7.9 Hz, 1H), 7.18 (d, J=7.5 Hz, 1H),7.05-6.88 (m, 3H), 6.78 (t, J=7.9 Hz, 2H), 6.65-6.55 (m, 2H), 4.96 and4.92 (2s, 4H). 59 376 521

N CH H N-(2-Amino-phenyl)-3- {6-[2-(pyrimidin-2- ylamino)-ethylamino]-pyridin-3-yl}- acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.29 (s,1H), 8.32 (d, J=4.9 Hz, 2H), 8.24 (d, J=1.9 # Hz, 1H), 7.71 (d, J=6.9Hz, 1H), 7.48 (d, J=15.7 Hz, 1H), 7.38 (d, J=7.7 Hz, 1H), 7.26 (bs, 2H),6.96 (t, J=6.9 Hz, 1H), 6.80 (dd, J=1.1, 7.7 Hz, 1H), 6.69-6.61 (m, 4H),5.00 (s, 2H), 3.52 (bs, 4H), 3 377 522

N CH H N-(2-Amino-phenyl)-3- {6-[2-(thiazol-2- ylamino)-ethylamino]-pyridin-3-yl}-acrylamide ¹H NMR (300 MHz, CD₃OD) δ (ppm): 8.12 (s, 1H),8.08 (s, 1H), 7.78 (d, J=8.8 Hz, 1H), 7.54 (d, J=15.4 Hz, 1H), # 7.19(d, J=8.0 Hz, 1H), 7.04 (t, J=7.4 Hz, 1H), 6.87 (d, J=8.0 Hz, 1H), 6.75(t, J=7.4 Hz, 1H), 6.64 (d, J=15.4 Hz, 1H), 6.65 (s, 1H), 4.90 (s, 5H),3.50-3.45 (m, 4H), 3.30 (d, J=1.3 Hz, 1H). 3 378 523

CH CH H N-(2-Amino-phenyl)-3- (4-{[(2-morpholin-4-yl- ethyl)-(3,4,5-trimethoxy-phenyl)- amino]-methyl}- phenyl)-acrylamide ¹H-NMR (CD₃OD), δ(ppm): 7.83 (d, J=15.6 Hz, 1H), 7.67 (d, J=7.8 Hz, 2H), 7.62-7.58 # (m,2H), 7.53-7.51 (m, 2H), 7.49 (d, J=7.8 Hz, 2H), 7.01 (d, J=15.6 Hz, 1H),), 4.99 (bs, 9H), 4.84 (bs, 2H), 4.22 (t, J=6.5 Hz, 2H), 4.05 (s, 4H),3.85 (s, 6H), 3.76 (s, 3H), 3.57-3.50 (m, 4H). 3, 33, 57 379 524

N CH H N-(2-Amino-phenyl)-3- [6-(3-hydroxy- benzylamino)-pyridin-3-yl-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.32 (s, 1H), 9.26 (s, 1H),8.19 (s, 1H), 7.66 (d, J=8.5 Hz, 1H), 7.57 (t, # J=6.0 Hz, 1H), 7.41 (d,J=15.7 Hz, 1H), 7.32 (d J=7.7 Hz), 7.10 (t, J=7.6 Hz, 1H), 6.91 (t,J=7.6 Hz, 1H), 6.75 (m, 3H), 6.59 (m, 4H), 4.98 (bs, 2H), 4.46 (d, J=5.8Hz, 2H). 3 380 525

N CH H N-(2-Amino-phenyl)-3- {6-[3-(2,2,2-trifluoro-ethoxy)-benzylamino]- pyridin-3-yl]- acrylamide ¹H-NMR (DMSO-d₆), δ(ppm): 9.25 (s, 1H), 8.18 (s, 1H), 7.67 (d, J=8.8 Hz, 1H), 7.59 (t, #J=6.0 Hz, 1H), 7.42 (d, J=15.7 Hz, 1H), 7.30 (m, 2H), 7.00 (m, 2H), 6.92(m, 2H), 6.74 (d, J=8.0 Hz, 1H), 6.60 (m, 3H), 4.92 (s, 2H), 4.73 (q,J=8.8 Hz, 2H), 4.52 (d, J=5.8 Hz, 2H). 3 381 526

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-hydroxy-4-(4-methyl-piperazin-1-yl)- phenylamino]-methyl}- phenyl)-acrylamide ¹H-NMR(CD₃OD), δ (ppm): 7.64 (d, J=15.6 Hz, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.49# (m, 1H), 7.40 (d, J=8.0 Hz, 2H), 7.21 (m, 2H), 7.03 (t, J=7.6 Hz, 1H),6.88-6.71 (m, 4H), 4.88 (bs, 4H), 4.34 (s, 2H), 2.86 (t, J=4.1 Hz, 4H),2.67 (bs, 4H), 2.41 (s, 3H). 3, 33, 58 382 527

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-fluoro-4-(4-methyl-piperazin-1-yl)- phenylamino]-methyl}- phenyl)-acrylamide ¹H-NMR(DMSO-d₆, δ (ppm): 9.43 (s, 1H), 7.61 (d, J=8.0 Hz, 2H), 7.45 (d, #J=8.0 Hz, 2H), 7.38 (d, J=7.6 Hz, 1H), 7.00-6.88 (m, 2H), 6.85-6.79 (m,2H), 6.63 (t, J=7.6 Hz, 1H), 6.44-6.30 (m, 3H), 4.99 (bs, 2H), 4.30 (d,J=5.5 Hz, 2H), 2.87 (bs, 4H), 2.55 (m, 4H), 2.27 (s, 3H). 3, 33, 58 383528

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-hydroxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (CDCl₃), δ (ppm): 7.49 (d, J=14.0 Hz, 1H); #7.32 (d, J=7.2 Hz, 2H), 7.15 (d, J=7.2 Hz, 2H), 7.05 (m, 1H), 6.96 (m,1H), 6.90 (m, 3H), 6.76 (m, 1H), 6.55 (d, J=14.0 Hz, 1H), 6.03 (m, 1H),5.99 (m, 1H), 4.30 (bs, 5H), 4.10 (s, 2H). 3, 33 384 529

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-trifluoromethyl-pyrimidin-2-ylamino)- methyl]-phenyl}- acrylamide ¹H-NMR (CD₃OD), δ(ppm): 7.73 (d, J=16.0 Hz, 1H); 7.63 (d, J=8.5 Hz, 1H), 7.58 (d, J=8.0Hz, 2H), # 7.46 (d, J=8.0 Hz, 2H), 7.38 (d, J=8.5 Hz, 1H), 7.20 (d,J=8.0 Hz, 1H), 7.03 (dt, J=7.7, 1.4 Hz, 1H), 6.89 (d, J=1.1 Hz, 1H),6.85 (m, 1H), 6.73 (dt, J=7.7, 1.1 Hz, 1H), 6.56 (d, J=16.0 Hz, 1H),5.27 (s, 2H), 4.87 (bs, 2H), 4.62 (s, 2H). 3, 33 385 530

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-hydroxymethyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.90(s, 1H), 7.58 (m, 3H), 7.43 (d, J=8.0 Hz, 2H); 7.37 # (d, J=8.0 Hz, 1H),7.11 (m, 1H), 7.00 (m, 3H), 6.85 (d, J=15.4 Hz, 1H), 6.63 (s, 1H), 6.51(d, J=7.4, Hz, 1H), 6.46 (d, J=7.7 Hz, 1H), 4.35 (s, 2H), 4.32 (s, 2H).3, 33 386 531

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-pyridin-4- ylmethyl-phenylamino)-methyl]-phenyl}- acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.66 (s, 1H),8.46 (d, J=4.7 Hz, 2H); 7.55 (d, J=8.0 Hz, 2H), 7.50 (d, J=15.7 Hz, 1H),# 7.39 (d, J=8.0 Hz, 2H), 7.28 (d, J=4.7 Hz, 2H), 7.00 (d, J=15.7 Hz,1H), 6.92 (d, J=6.9 Hz, 2H), 6.90 (m, 1H), 6.75 (d, J=8 Hz, 1H), 6.58(m, 2H), 6.52 (d, J=6.9, Hz, 2H), 6.10 (bs, 1H), 4.26 (bs, 2H), 3.80 (s,2H), 2.08 (d, J=1.9 Hz, 2H). 3, 33 387 532

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-cyano- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.38 (s, 1H), 7.58 (d,J=7.7 Hz, 2H); 7.54 (d, J=15.9 Hz, 1H), 7.41 # (d, J=7.7 Hz, 2H), 7.33(d, J=8.0 Hz, 1H), 7.24 (t, J=7.7 Hz, 1H), 6.92-6.83 (m, 5H), 6.75 (d,J=8.0 Hz, 1H), 6.58 (t, J=7.4 Hz, 1H), 4.95 (bs, 2H), 4.34 (d, J=5.8 Hz,2H). 3, 33 388 533

CH CH H 3-(4-{[3-(Acetylamino- methyl)-phenylamino]-methyl}-phenyl)-N-(2- amino-phenyl)-acrylamide ¹H-NMR (DMSO-d₆), δ(ppm): 9.37 (bs, 1H), 8.21 (t, J=5.8 Hz, 1H), 7.56 (d, J=7.7 Hz, 2H),7.53 (d, J=15.7 Hz, 1H), 7.41 (d, J=8.0 # Hz, 2H), 7.33 (d, J=7.1 Hz,1H), 6.97 (m, 1H), 6.85 (d, J=15.7 Hz, 1H), 6.74 (dd, J=1.4, 8.0 Hz,1H), 6.58 (dt, J=1.4, 8.0 Hz, 1H), 6.50 (bs, 1H), 6.41 (d, J=8.0 Hz,2H), 6.30 (t, J=6.0 Hz, 1H), 4.94 (bs, 2H), 4.28 (d, J=6.0 Hz, 2H), 4.09(d, J=6.0 Hz, 2H), 1.83 (s, 3H). 3, 33 389 534

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-nitro-3- trifluoromethyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.37(bs, 1H), 7.56 (d, J=8.0 Hz, 2H), 7.53 (d, J=15.7 Hz, 1H), 7.41 # (d,J=8.0 Hz, 2H), 7.33 (d, J=7.7 Hz, 1H), 6.92 (d, J=7.7 Hz, 2H), 6.85 (d,J=15.7 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.67-6.55 (m, 4H), 5.84 (t,J=5.8 Hz, 1H), 4.94 (bs, 2H), 4.22 (d, J=5.8 Hz, 2H). 3, 33 390 535

CH CH H N-(2-Amino-phenyl)-3- {4-[(3,5-dichloro- phenylamino)-methyl]-phenyl)-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.39 (bs, 1H), 7.60 (d,J=8.0 Hz, 2H), 7.54 (d, J=15.7 Hz, 1H), 7.40 # (d, J=8.0 Hz 2H), 7.33(d, J=7.1 Hz, 1H), 6.97-6.89 (m, 2H), 6.87 (d, J=15.7 Hz, 1H), 6.75 (dd,J=1.4, 8.0 Hz, 1H), 6.60-6.55 (m, 4H), 4.95 (bs, 2H), 4.33 (d, J=6.0 Hz,2H). 3, 33 391 536

CH CH H N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)-vinyl]-phenyl]- acrylamide ¹H-NMR (CDCl₃), δ (ppm): 8.12 (bs, 1H), 7.64# (d, J=14.2 Hz, 1H), 7.42 (bs, 4H), 7.23 (bs, 2H), 6.97 (d, J=14.2 Hz,1H), 6.94-6.82 (m, 4H), 6.70 (s, 2H), 4.11 (bs, 2H), 3.87 (s, 6H), 3.84(s, 3H). 3 392 537

CH CH H N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)-vinyl]-phenyl}- acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 8.49 (s, 1H), 7.58(d, J=15.7 Hz, # 1H), 7.33 (d, J=8.5 Hz, 1H), 7.23 (m, 4H), 7.00 (d,J=8.5 Hz, 1H), 6.73 (d, J=5.0 Hz, 2H), 6.69 (d, J=5.0 Hz, 2H), 6.58 (d,J=15.4 Hz, 1H), 6.53 (bs, 2H), 6.47 (s, 2H), 3.85 (s, 3H), 3.63 (s, 6H).3 393 538

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-sulfamoyl- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (CD₃OD/CDCl₃), δ (ppm): 7.61 (d, J=15.7 # Hz,1H), 7.45 (d, J=8.1 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.18 (dd, J=8.0 Hz,2H), 7.12 (d, J=15.7 Hz, 1H), 7.10 (m, 1H), 7.03 (t, J=7.4 Hz, 1H),6.83-6.66 (m, 4H), 3.93 (bs, all NH signals). 1, 3, 33 394 539

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-(3-morpholin-4-yl-propylsulfamoyl)- phenylamino]-methyl}- phenyl)-acrylamide ¹H-NMR(CDCl₃), δ (ppm): 8.34 (bs, 1H), 7.64 (d, J=15.4 Hz, 1H), 7.37 # (d,J=8.0 Hz, 2H), 7.34 (m, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.23 (d, J=15.4 Hz,1H), 7.14 (d, J=7.8 Hz, 1H), 7.04 (m, 2H), 6.74 (m, 4H), 4.85 (bs, 1H),4.30 (d, J=4.4 Hz, 2H), 3.69 (t, J=4.4 Hz, 4H), 2.99 (t, J=5.8 Hz, 2H),2.40 (bs, 6H), 1.59 (t, J=4.4 Hz, 2H). 3, 33, 42 395 540

CH CH H N-(2-Amino-phenyl)-3- {4-[2-(3,4,5- trimethoxy-phenyl)-ethyl]-phenyl}- acrylamide ¹H-NMR (CDCl₃), δ (ppm): 8.53 (s, 1H), 7.72(d, # J=15.6 Hz, 1H), 7.38 (d, J=7.7 Hz, 2H), 7.33 (m, 1H), 7.16 (d,J=7.7 Hz, 2H), 7.07 (m, 1H), 6.79 (m, 2H), 6.69 (d, J=15.6 Hz, 1H), 6.41(s, 2H), 4.04 (bs, 2H), 3.91 (s, 3H), 3.85 (s, 6H), 2.94 (m, 4H). 3, 32396 541

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-methoxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.35 (s, 1H), 7.56 (d,J=7.5 Hz, 2H), 7.52 (d, J=15.4 Hz, 1H), 7.40 (d, J=7.5 # Hz, 2H), 7.33(d, J=7.7 Hz, 1H), 6.92 (d, J=7.7 Hz, 1H), 6.85 (d, J=15.4 Hz, 1H), 6.75(d, J=8.0 Hz, 1H), 6.67 (d, J=8.6 Hz, 2H), 6.58 (m, 1H), 6.52 (d, J=8.6Hz, 2H), 5.84 (t, J=5.5 Hz, 1H), 4.23 (d, J=5.5 Hz, 2H), 3.61 (s, 3H).3, 33 397 542

CH CH H N-(2-Amino-phenyl)-3- {4-[(3,4-dimethoxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (CDCl₃), δ (ppm): 8.48 (s, 1H), 7.60 (d,J=15.4 Hz, 1H), 7.27 (m, 5H), 6.97 # (t, J=7.5 Hz, 1H), 6.70 (m, 3H),6.59 (d, J=15.4 Hz, 1H), 6.25 (s, 1H), 6.12 (d, J=7.1 Hz, 1H), 4.23 (s,2H), 3.93 (bs, 3H), 3.75 (s, 3H), 3.73 (s, 3H). 3, 33 398 543

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-(1H-tetrazol-5-yl)-phenylamino]-methyl}- phenyl)-acrylamide ¹H-NMR (CD₃OD), δ (ppm): 7.75(d, J=15.2 # Hz, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.48 (d, J=7.6 Hz, 2H),7.33 (m, 3H), 7.27 (m, 3H), 7.20 (m, 1H), 6.84 (m, 2H), 5.48 (bs, 5H),4.46 (s, 2H). 3, 33 399 544

CH CH H N-(2-Amino-phenyl)-3- (4-{[4-(1H-tetrazol-5- ylmethyl)-phenylamino]-methyl}- phenyl)-acrylamide ¹H-NMR (CD₃OD), δ (ppm): 7.75(d, J=15.2 Hz, 1H), 7.58 (d, J=8.2 Hz, 2H), 7.42 # (d, J=8.2 Hz, 2H),7.29 (m, 2H), 7.20 (m, 2H), 7.04 (d, J=8.2 Hz, 2H), 6.83 (d, J=15.2 Hz,1H), 6.67 (d, J=8.2 Hz, 2H), 5.48 (bs, 5H), 4.39 (s, 2H). 4.16 (s, 2H).3, 33 400 545

CH CH H N-(2-Amina-phenyl)-3- {4-[(4-bromo- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.42 (s, 1H), 7.62(d, J=8.5 Hz, 2H), 7.59 (d, J=15.6 Hz, 1H), # 7.45 (d, J=8.0 Hz, 2H),7.40 (d, J=7.5 Hz, 1H), 7.23 (d, J=8.5 Hz, 2H), 6.98 (d, J=7.5 Hz, 1H),6.92 (d, J=15.6 Hz, 1H), 6.80 (d, J=8.0 Hz, 1H), 6.66-6.57 (m, 4H), 4.99(bs, 2H), 4.34 (d, J=5.8 Hz, 2H). 3, 33 401 546

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-bromo- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.36 (s, 1H), 7.57(d, J=7.6 Hz, 2H), 7.54 (d, J=15.8 # Hz, 1H), 7.40 (d, J=8.2 Hz, 2H),7.33 (d, J=7.6 Hz, 1H), 7.00-6.91 (m, 2H), 6.86 (d, J=15.8 Hz, 1H), 6.74(d, J=8.2 Hz, 2H), 6.66-6.54 (m, 4H), 4.93 (bs, 2H), 4.30 (d, J=5.3 Hz,2H). 3, 33 402 547

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-iodo- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.36 (s, 1H), 7.56(d, J=8.0 Hz, 2H), 7.53 (d, J=15.8 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), #7.35 (m, 1H), 7.31 (d, J=8.2 Hz, 2H), 6.92 (d, J=7.1 Hz, 1H), 6.85 (d,J=15.8 Hz, 1H), 6.75 (d, J=7.7 Hz, 1H), 6.57 (t, J=8.0 Hz, 1H), 6.52 (t,J=6.0 Hz, 1H), 6.42 (d, J=8.5 Hz, 2H), 4.94 (bs, 2H), 4.28 (d, J=6.0 Hz,2H). 3, 33 403 548

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-iodo- phenylamino)-methyl]-phenyl]-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.40 (s, 1H), 7.57(d, J=7.6 # Hz, 2H), 7.53 (d, J=15.6 Hz, 1H), 7.40 (d, J=8.2 Hz, 2H),7.33 (d, J=7.6 Hz, 1H), 6.92 (m, 3H), 6.84 (m, 2H), 6.74 (d, J=7.6 Hz,1H), 6.60-6.50 (m, 3H), 4.93 (bs, 2H), 4.28 (d, J=5.9 Hz, 2H). 3, 33 404549

CH CH H N-(2-Amino-phenyl)-3- (4-{[3-(2-hydroxy- ethoxy)-phenylamino]-methyl}-phenyl)- acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.42 (s,1H), 7.63 (d, J=8.2 Hz, 2H), 7.60 (d, J=15.3 Hz, 1H), 7.46 # (d, J=8.2Hz, 2H), 7.40 (d, J=7.6 Hz, 1H), 7.03-6.98 (m, 2H), 6.91 (d, J=15.3 Hz,1H), 6.81 (d, J=7.6 Hz, 1H), 6.64 (t, J=7.6 Hz, 1H), 6.36 (t, J=5.9 Hz,1H), 6.28-6.22 (m, 3H), 4.99 (bs, 3H), 4.61 (s, 2H), 4.34 (d, J=5.0 Hz,2H) 4.28 (d, J=5.0 Hz, 2H). 3, 33 405 550

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-ntro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.38 (s, 1H), 7.99(d, J=9.1 Hz, 2H), 7.85 (t, J=5.9 Hz, 1H), 7.60 (d, J=7.6 Hz, 2H), 7.54(d, # J=15.8 Hz, 1H), 7.40 (d, J=7.6 Hz, 2H), 7.34 (d, J=7.6 Hz, 1H),6.94-6.92 (m, 1H), 6.88 (d, J=15.8 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.68(d, J=9.1 Hz, 2H), 6.58 (t, J=7.6 Hz, 1H), 4.94 (bs, 2H), 4.46 (d, J=5.9Hz, 2H) 3, 33 406 551

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-nitro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.37 (s, 1H), 7.59(d, J=7.6 Hz, 2H), 7.54 (d, J=15.2 Hz, 1H), # 7.43 (d, J=7.6 Hz, 2H),7.36-7.28 (m, 4H), 7.05-6.98 (m, 2H), 6.92 (d, J=7.6 Hz, 1H), 6.88 (d,J=15.2 Hz, 1H), 6.75 (d, J=7.6 Hz, 1H), 6.58 (t, J=7.6 Hz, 1H), 4.96(bs, 2H), 4.39 (d, J=5.3 Hz, 2H). 3, 33 407 552

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-chloro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.43 (s, 1H), 7.62(d, J=7.6 Hz, 2H), 7.59 (d, J=15.8 Hz, 1H), 7.46 (d, J=7.6 Hz, 2H), 7.40(d, J=7.6 Hz, # 1H), 7.12 (d, J=8.8 Hz, 2H), 6.98 (d, J=7.6 Hz, 1H),6.93 (d, J=15.8 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.62 (d, J=8.8 Hz, 2H),6.55 (bs, 2H), 4.99 (bs, 2H), 4.46 (d, J=5.9 Hz, 2H), 4.35 (d, J=5.9 Hz,2H) 3, 33 408 553

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-chloro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.50 (s, 1H), 7.65(d, J=8.2 Hz, 2H), 7.61 (d, # J=15.4 Hz, 1H), 7.47 (d, J=7.6 Hz, 2H),7.43 (m, 1H), 6.93 (d, J=7.0 Hz, 1H), 6.79 (d, J=15.4 Hz, 1H), 6.68 (m,3H), 6.59 (m, 3H), 5.24 (bs, 2H), 4.31 (s, 2H). 3, 33 409 554

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-fluoro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.37(s, 1H), 7.63(d, J=8.2 Hz, 2H), 7.60 (d, # J=15.4 Hz, 1H), 7.47 (d, J=7.6 Hz, 2H),7.41 (m, 1H), 7.01-6.90 (m, 4H), 6.75 (d, J=7.6 Hz, 1H), 6.67-6.59 (m,3H), 6.27 (bs, 1H), 4.95 (bs, 2H), 4.27 (s, 2H). 3, 33 410 555

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-methylsulfanyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H NMR (300 MHz, CD₃OD) δ(ppm): 7.64 (d, J=15.9 Hz, 1H), 7.47 (d, J=7.5 Hz, 2H), 7.32 (d, J=7.5Hz, 2H), 7.19 (d, J=7.5 Hz, 1H), # 7.03 (t, J=7.8 Hz, 1H), 6.82 (d,J=7.5 Hz, 1H), 6.77 (d, J=7.8 Hz, 1H), 6.70 (d, J=15.9 Hz, 1H), 6.56 (d,J=7.8 Hz, 1H), 6.49 (s, 1H), 6.37 (d, J=7.8 Hz, 1H), 4.29 (s, 2H), 4.05(bs, 4H), 2.37 (s, 3H). 3, 33 411 556

CH CH H N-(2-Amino-phenyl)-3- {4-[(4-methylsulfanyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 9.36 (s, 1H), 7.57 (d, J=7.5 Hz, 2H), 7.53 (d, J=15.8 Hz, 1H),7.40 (d, # J=7.9 Hz, 2H), 7.34 (d, J=7.9 Hz, 1H), 7.07 (d, J=8.3 Hz,2H), 6.92 (d, J=7.5 Hz, 1H), 6.87 (d, J=15.8 Hz, 1H), 6.75 (d, J=7.9 Hz,1H), 6.60-6.54 (m, 3H), 6.39 (t, J=5.7 Hz, 1H), 4.93 (bs, 2H), 4.29 (d,J=6.1 Hz, 2H), 2.32 (s, 3H),. 3, 33 412 557

CH CH H N-(2-Amino-phenyl)-3- {4-[(5-bromo-pyridin-2- ylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.36 (s, 1H), 8.02(d, J=1.7 Hz, 1H), 7.57-7.50 (m, 4H), # 7.38-7.32 (m, 4H), 6.92 (d,J=7.5 Hz, 1H), 6.86 (d, J=16.3 Hz, 1H), 6.75 (d, J=7.9 Hz, 1H), 6.59 (d,J=7.5 Hz, 1H), 6.53 (d, J=9.2 Hz, 1H), 4.94 (bs, 2H), 4.48 (d, J=5.7 Hz,2H). 3, 33 413 558

CH CH H N-(2-Amino-phenyl)-3- [4-(naphthalen-1- ylaminomethyl)-phenyl]-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.37 (s, 1H), 8.25(m, 1H), 7.76 (m, 1H), 7.57 (m, 2H), 7.47 (m, 4H), 7.33 (d, J=7.0 Hz,1H), # 7.17 (m, 1H), 7.07 (d, J=8.2 Hz, 1H), 6.99 (t, J=5.3 Hz, 1H),6.92 (d, J=7.0 Hz, 1H), 6.85 (d, J=16.4 Hz, 1H), 6.74 (d, J=7.6 Hz, 1H),6.57 (t, J=7.6 Hz, 1H), 6.36 (t, J=7.6 Hz, 1H), 4.90 (s, 2H), 4.54 (d,J=5.3 Hz, 2H). 3, 33 414 559

CH CH H N-(2-Amino-phenyl)-3- {4-[(3-fluoro- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.39 (s, 1H), 7.57(d, J=7.0 Hz, 2H), 7.53 (d, J=15.4 Hz, 1H), # 7.40 (d, J=7.6 Hz, 2H),7.36 (d, J=7.6 Hz, 1H), 7.02 (q, J=7.6 Hz, 1H), 6.90 (m, 2H), 6.76 (d,J=8.2 Hz, 1H), 6.58 (m, 1H), 6.40 (d, J=8.2 Hz, 1H), 6.29 (m, 2H), 4.90(s, 1H), 4.29 (bs, 2H), 4.02 (s, 2H). 3, 33 415 560

N-(2-Amino-phenyl)-3-{3,5- dimethoxy-4-[(3,4,5- trimethoxy-phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (CDCl₃), δ (ppm): # 7.73 (bs, 1H),7.63 (d, J=14.9 Hz, 1H), 6.81 (m, 3H), 6.70 (m, 2H), 6.68-6.56 (m, 2H),6.07 (s, 2H), 4.35 (s, 2H), 3.86 (s, 6H), 3.81 (s, 6H), 3.75 (s, 3H). 60416 561

N-(2-Amino-3-hydroxy- phenyl)-3-{4-[(3,4,5- trimethoxy-phenylamino)-methyl]-phenyl}- acrylamide ¹H NMR (300 MHz, CDCl₃) δ (ppm): 9.22 (s,1H), 9.11 (s, 1H), 7.57 (d, J=7.9 Hz, 2H), 7.64 (d, J=15.8 Hz, # 1H),7.44 (d, J=7.9 Hz, 2H), 6.96 (d, J=15.8 Hz, 1H), 6.78 (t, J=7.9 Hz, 1H),6.23 (t, J=7.9 Hz, 1H), 6.16 (d, J=7.9 Hz, 1H), 6.09 (t, J=6.2 Hz, 1H),5.89 (s, 2H), 4.77 (bs, 2H), 4.27 (d, J=5.7 Hz, 2H), 5.89 (s, 6H), 5.76(s, 3H). 3, 33 417 562

CH CH H N-(2-Amino-phenyl)-3-(4- [(2,3,4-trimethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H NMR (300 MHz, CDCl₃) δ(ppm): 8.25 (s, 1H), 7.74 (d, J=15.5 Hz, 1H), 7.44 (d, J=7.9 Hz, 2H),7.37 (d, J=7.9 Hz, 2H), 7.34-7.29 (m, 2H), 7.08 # (t, J=7.5 Hz, 1H),6.82 (t, J=7.5 Hz, 1H), 6.79 (m, 1H), 6.66 (d, J=15.5 Hz, 1H), 6.60 (d,J=8.8 Hz, 1H), 6.31 (d, J=8.8 Hz, 1H), 4.36 (s, 2H), 4.18 (bs, 2H), 3.98(s, 3H), 3.96 (s, 3H), 3.84 (s, 3H). 3, 33 418 563

CH CH H N-(2-Amino-phenyl)-3-[4-({4- methoxy-3-[(3,4,5-trimethoxy-phenylamino)- methyl]-phenylamino}-methyl)-phenyl]-acrylamide ¹H NMR (300 MHz, CDCl₃) δ (ppm): 8.58 (s,1H), 7.66 (d, J=15.4 Hz, 1H), 7.33-7.28 (m, 3H), # 7.23 (d, J=7.0 Hz,2H), 7.04 (t, J=7.0 Hz, 1H), 6.77-6.70 (m, 4H), 6.64 (d, J=15.4 Hz, 1H),6.53 (d, J=7.5 Hz, 1H), 5.90 (s, 2H), 4.27 (s, 2H), 4.25 (s, 2H), 4.08(bs, 4H), 3.82 (s, 6H), 3.77 (s, 6H). 3, 33 419 564

N-(2,3-Diamino-phenyl)-3- {4-[(3,4,5-trimethoxy- phenylamino)-methyl]-phenyl}-acrylamide ¹H NMR (300 MHz, CDCl₃) δ (ppm): 7.64 (d, J=15.4 Hz,1H), 7.48 (d, J=7.5 Hz, 2H), 7.35 (d, J=7.5 Hz, # 2H), 7.31-7.24 (m,2H), 6.86 (s, 1H), 6.73 (d, J=15.4 Hz, 1H), 5.84 (s, 2H), 4.27 (s, 2H),4.00 (bs, 6H), 3.71 (s, 6H), 3.68 (s, 3H). 3, 33 420 565

CH CH H N-(2-Amino-phenyl)-3-{4-[(3- fluoro-4-methylsulfanyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.38(bs, 1H), 7.58 (d, J=7.5 Hz, 2H), 7.54 (d, J=15.4 Hz, 1H), 7.40 (d,J=7.9 Hz, 2H), 7.33 (d, J=7.9 Hz, 1H), # 7.14 (t, J=8.3 Hz, 1H),6.94-6.89 (m, 2H), 6.81 (d, J=15.7 Hz, 1H), 6.74 (d, J=8.3 Hz, 1H), 6.58(t, J=7.5 Hz, 1H), 6.43-6.38 (m, 2H), 4.94 (bs, 2H), 4.30 (d, J=5.7 Hz,2H). 2.28 (s, 3H). 3, 33 421 566

CH CH H N-(2-Amino-phenyl)-3-{4-[(4- methylsulfanyl-3- trifluoromethyl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.39(bs, 1H), 7.59 (d, J=7.9 Hz, 2H), 7.54 (d, J=15.8 Hz, 1H), 7.41 (d, #J=7.9 Hz, 2H), 7.36 (d, J=7.9 Hz, 1H), 7.33 (d, J=6.2 Hz, 1H), 6.96-6.90(m, 4H), 6.82 (d, J=15.8 Hz, 1H), 6.79-6.74 (m, 1H), 6.58 (t, J=7.5 Hz,1H), 4.95 (bs, 2H), 4.35 (d, J=6.2 Hz, 2H). 2.35 (s, 3H). 3, 33 422 567

N-(2-Amino-phenyl)-3-{3- nitro-4-[(3,4,5-trimethoxy-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.50(s, 1H), 8.09 (s, 1H), 7.80 (d, J=15.4 Hz, 1H), 7.81 (s, 2H), 7.34 (d,J=7.9 Hz, 1H), 6.94 (d, # J=7.5 Hz, 1H), 6.88 (d, J=15.4 Hz, 1H), 6.76(d, J=7.9 Hz, 1H), 6.58 (t, J=7.5 Hz, 1H), 6.26 (t, J=6.2 Hz, 1H), 5.90(s, 2H), 4.96 (bs, 2H), 4.39 (d, J=5.7 Hz, 2H), 3.66 (s, 6H), 3.51 (s,3H). 3, 33 423 568

N-(2-Amino-phenyl)-3-{3- amino-4-[(3,4,5- trimethoxy-phenylamino)-methyl]-phenyl}-acrylamide ¹H-NMR (DMSO-d₆), δ (ppm): 9.29 (s, 1H), 7.72(d, J=15.4 Hz, 1H), 7.33 (m, 2H), 6.90 (1H); 6.71 (2H), # 6.62 (3H),5.97 (1H), 5.87 (2H), 5.49 (2H), 4.96 (2H), 4.10 (2H), 3.65 (6H), 3.51(3H). 3, 33 424 569

N-(2-Amino-phenyl)-3-[6- (3,4-dimethoxy-phenyl)-pyridin-3-yl]-acrylamide LRMS: calc: 375.4, found: 376.4 3, 15, 33 425570

N-(4-Amino-thiophen-3-yl)- 3-{4-[(4-morpholin-4-yl-phenylamino)-methyl]- phenyl}-acrylamide ¹H-NMR (DMSO-d6), δ (ppm): 9.64(bs, 1H), 7.65 (d, J=7.9 Hz, 2H), 7.60 # (d, J=14.0 Hz, 1H), 7.50 (d,J=7.9 Hz, 2H), 6.90 (d, J=15.8 Hz, 1H), 6.15 (d, J=4.0 Hz, 1H), 5.95 (s,2H), 5.82 (s, 1H), 4.89 (bs, 2H), 4.33 (d, J=5.7 Hz, 2H), 3.71 (s, 6H),3.57 (s, 3H). 3, 33, 60

[0391]

Example 85N-(2-Amino-phenyl)-4-(1H-benzimidazol-2-ylsulfanylmethyl)-benzamide(compound 126)

[0392] Step 1: 4-(1H-Benzimidazol-2-ylsulfanylmethyl)-benzoic acidmethyl ester (compound 122)

[0393] Following the procedure described in Example 47, step 2, butusing 119 and substituting 121 for 63, the title compound 122 wasobtained in 95% yield. LRMS=299.1 (M+1).

[0394] Step 2:N-(2-Amino-phenyl)-4(1H-benzimidazol-2-ylsulfanylmethyl)-benzamide (126)

[0395] Following the procedure described in Example 1, steps 4 and 5,but substituting 122 for 6, the title compound 126 was obtained in 62%yield. ¹H NMR: (DMSO-d₆) δ(ppm): 9.57 (s, 1H), 7.89 (d, J=8.2 Hz, 2H),7.55 (d, J=8.2 Hz, 2H), 7.53 (bs, 2H), 7.36 (bs, 2H), 7.14-7.08 (m, 3H),6.94 (t, J=8.2 Hz, 1H), 6.74 (d, J=6.9 Hz, 1H), 6.56 (t, J=8.0 Hz, 1H),4.87 (bs, 2H), 4.62 (s, 2H).

Example 87N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide(compound 128)

[0396] Step 1: 4-(6-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic acidmethyl ester (122)

[0397] Following the procedure described in Example 47, step 2, butusing 120 and substituting 121 for 63, the title compound 122 wasobtained in 45% yield. LRMS=331.0 (M+1).

[0398] Step 2:4-[6-(2-Morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]-benzoicacid methyl ester (compound 124)

[0399] To a solution of4-(6-Amino-benzothiazol-2-ylsulfanylmethyl)-benzoic acid methyl ester122 (800 mg, 2.42 mmol), in DMF (24 mL), were added successively solid4-(2-chloroethyl)morpholine hydrochloride (296 mg, 2.66 mmol), K₂CO₃(611 mg, 5.08 mmol), Nal (363 mg, 2.42 mmol), Et₃N (370 μL, 2.66 mmol)and tetrabutylammonium iodide (894 mg, 2.42 mmol), The mixture wasstirred at 120° C. for 24 h and more 4-(2-chloroethyl)morpholinehydrochloride (296 mg, 2.66 mmol) was added. The mixture was stirred for8 h at 120° C. and the solvent was removed in vacuo. The resulting blacksyrup was partitioned between H₂O and EtOAc. The organic layer wassuccessively washed with HCl 1N and saturated aqueous NaHCO₃. Theprecipitate was extracted twice with EtOAc, dried over MgSO₄ andconcentrated. Purification by flash chromatography (MeOH/CHCl₃: 5:95 to10:90) afforded 48 mg (4% yield) of 124 as a light yellow oil.LRMS=444.1 (M+1).

[0400] Step 3:N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethylamino)-benzothiazol-2-ylsulfanylmethyl]-benzamide(compound 128)

[0401] Following the procedure described in Example 1, steps 4 and 5,but substituting 124 for 6, the title compound 128 was obtained in 76%yield. ¹H NMR: (Acetone-d₆) δ(ppm): 9.06 (bs, 1H), 7.98 (d, J=8.2 Hz,2H), 7.63 (d, J=8.5 Hz, 2H), 7.62 (d, J=8.8 Hz, 2H), 7.29 (d, J=8.0 Hz,1H), 7.06 (d, J=2.2 Hz, 1H), 7.02-6.97 (m, 1H), 6.87-6.82 (m, 2H), 6.66(dt, J=7.4 Hz, 1.4 Hz, 1H), 4.63 (s, 2H), 3.64-3.60 (m, 4H), 3.25 (t,J=6.3 Hz, 2H), 2.63 (t, J=6.3 Hz, 2H), 2.54-2.42 (m, 4H).

Example 88 N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide(compound 131)

[0402] Step 1: 2-(4-Bromo-benzylsulfanyl)-quinoline (compound 130)

[0403] Following the procedure described in Example 47, step 2, butsubstituting 129 for 63, the title compound 130 was obtained in 89%yield. LRMS=332.0 (M+1).

[0404] Step 2:N-(2-Amino-phenyl)-4-(quinolin-2-ylsulfanylmethyl)-benzamide (131)

[0405] Following the procedure described in Example 40, step 2, butsubstituting 129 for 42, the title compound 131 was obtained in 70%yield. ¹H NMR: (DMSO-d₆) δ(ppm): 9.62 (bs, 1H), 8.21 (d, J=8.8 Hz, 1H),8.00-7.89 (m, 4H), 7.79 (dd, J=6.8 Hz, 1.3 Hz, 1H), 7.68 (d, J=6.3 Hz,2H), 7.56 (t, J=6.8 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.2 Hz,1H), 6.99 (dt, J=7.9 Hz, 7.4 Hz, 1H), 6.79 (d, J=6.9 Hz, 1H), 6.61 (dt,J=7.7 Hz, 7.4 Hz, 1H), 4.69 (s, 2H).

Example 89 N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide(compound 134)

[0406] Step 1: 4-(Pyrimidin-2-ylaminomethyl)-benzoic acid methyl ester(compound 133)

[0407] Following the procedure described in Example 47, step 2, butsubstituting 132 for 63, the title compound 133 was obtained in 76%yield. LRMS=244.2 (M+1).

[0408] Step 2:N-(2-Amino-phenyl)-4-(pyrimidin-2-ylaminomethyl)-benzamide (134)

[0409] Following the procedure described in Example 1, steps 4 and 5,but substituting 129 for 6, the title compound 134 was obtained in 91%yield. ¹H NMR: (DMSO-d₆) δ(ppm): 9.6 (bs, 1H), 8.32 (d, J=4.9 Hz, 2H),7.97 (dt, J=9.9 Hz, 7.9 Hz, 2H), 7.85-7.83 (m, 1H), 7.47, (d, J=8.2 Hz,2H), 7.20 (d, J=7.9 Hz, 1H), 7.01 (dt, J=7.7 Hz, 7.4 Hz, 1H) 6.82 (d,J=7.9 Hz, 1H), 6.66-6.62 (m, 1H), 4.98 (bs, 2H), 4.61 (d, 2H).

Example 90N-(2-Amino-phenyl)-4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl]-benzamide(compound 139)

[0410] Step 1: [2-(4-lodo-benzoylamino)-phenyl]-carbamic acid tert-butylester (compound 135)

[0411] To a solution of di-tert-butyldicarbonate (39 g, 181 mmol) in THF(139 mL) placed in a water bath, was added 1,2-phenylenediamine (15 g,139 mmol) and DMAP (1.7 g, 14 mmol). The mixture was stirred at r.t. for16 h and the solvent was removed in vacuo. The crude material waspartitioned between EtOAc and water. The organic layer was washed withHCl 1 N and then with aqueous saturated NaHCO₃. The combined organiclayers were washed with brine, dried over MgSO₄ and concentratedaffording the compound (18.9 g, 65% yield) as a light beige powder.LRMS=209.1 (M+1).

[0412] To a solution of 4-iodobenzoic acid (8.0 g, 32.3 mmol) in DMF (65mL) at r.t., were successively added1-[3-(dimethylamino)propyl]-3-ethylcabodiimide hydrochloride (8.0 g,41.9 mmol) and 1-hydroxybenzotriazole (5.2 g, 38.7 mmol). The mixturewas stirred for 1 h and a solution of (2-amino-phenyl)-carbamic acidtert-butyl ester (6.3 g, 30.2 mmol) in DMF (20 mL) was added to themixture via cannula, followed by triethylamine (5.9 mL, 4.9 mmol). Themixture was stirred for 16 h and the solvent was removed in vacuo. Thecrude material was partitioned between chloroform and water. The organiclayer was washed with aqueous saturated NaHCO₃, dried over MgSO₄ andconcentrated to a light brown syrup which was crystallized in hot EtOAcor Et₂O, yielding 135 (9.3 g, 70% yield) as a white solid. LRMS=461.0(M+Na⁺).

[0413] Step 2: N-[2-tert-butoxycarbonylamino-phenyl)-terephtalamic acidmethyl ester (compound 136)

[0414] Following the procedure described in Example 40, step 2, butsubstituting 135 for 42, the title compound 136 was obtained in 95%yield. LRMS=393.1 (M+Na⁺).

[0415] Step 3: [2(4-Hydroxymethyl-benzoylamino)-phenyl]-carbamic acidtert-butyl ester (137)

[0416] To a solution of 136 (7.5g, 20.6 mmol) in THF (40 mL), cooleddown to −20° C. under N₂, was added a 1M solution of DIBAL-H (122 mL,122 mmol) in toluene. After stirring for 18 h. at r.t., the mixture wascooled down to 0° C. and carefully quenched by a dropwise addition ofH₂O (10 mL) and of 2N NaOH (5 mL). The aluminum salts were allowed todecant and the supernatant was removed. The organic layer was washedwith H₂O, 1 N HCl (6 times), satd. aqueous NaHCO₃, brine, dried overMgSO₄ and concentrated (2.04 g, 43%). Purification of the crude materialby flash chromatography (EtOAc/hexanes 50:50 to 70:30) afforded 137(1.14 g, 16% yield) as a solid foam. LRMS=365.2 (M+Na⁺).

[0417] Step 4:{2-[4-(1-Methyl-imidazol-2-ylsulfanylmethyl)-benzoylamino]-phenyl}-carbamicacid tert-butyl ester (compound 138)

[0418] To a solution of N-methyl-2-mercaptoimidazole (28 mg, 0.25 mmol)in THF (1 mL), at r.t. under N₂atmosphere were successively added 137(70 mg, 0.20 mmol), triphenylphosphine (70 mg, 0.27 mmol) followed bydropwise addition of diethyl azodicarboxylate (48 μL, 0.31 mmol). Themixture was stirred for 2 h and the solvent was removed in vacuo.Purification by flash chromatography using MeOH/CHCl₃ (5:95) as theeluent afforded the title compound 138 (81 mg), in 91% yield, which wasfound to contain some diethyl hydrazodicarboxylate residus. The compoundwas used as is without further purification.

[0419] Step 5:N-(2-Amino-phenyl-4-(1-methyl-1H-imidazol-2-ylsulfanylmethyl]-benzamide(compound 139)

[0420] Following the procedure described in Example 42, step 3, butsubstituting 138 for 46, the title compound 139 was obtained in 62%yield. ¹H NMR: (Acetone-d₆) δ(ppm): 9.07 (bs, 1H), 7.93 (d, J=8.2 Hz,2H), 7.37 (d, J=8.2 Hz, 2H), 7.29 (d, J=8.0 Hz, 1H), 7.10 (d, J=1.1 Hz,1H), 7.03-6.96 (m, 2H), 6.86 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.67 (dt, J=7.4Hz, 1.1 Hz, 1H), 4.63 (bs, 2H), 4.29 (s, 2H), 3.42 (s, 3H).

Example 91 N-(2-Amino-phenyl)-6-(3-methoxyphenyl)-nicotinamide (compound141)

[0421] To a mixture of 3-methoxyphenyl boronic acid (152 mg, 1.0 mmol)and 140 (248 g, 1.0 mmol) were added benzene (8 mL) and ethanol (4 mL)followed by 2 M Na₂CO₃ aqueous solution (3.2 mL, 6.4 mmol). The reactionmixture was stirred under nitrogen for 30 min and then Pd(PPh₃)₄ (58 mg,0.05 mmol) was quickly added. After 24 h of reflux, the mixture wascooled to room temperature, filtered through a pad of celite and rinsedwith ethyl acetate (30 mL). The organic solution was washed with brine(5 mL), dried (MgSO₄), and concentrated. Purification by flash silicagel chromatography (Hexane/Ethyl acetate: 1/1) afforded 141 (302 mg, 95%yield). ¹H NMR (CDCl₃) δ(ppm): 9.11 (d, J=1.8 Hz, 1H), 8.30 (dd, J=8.4Hz, 1.8 Hz, 1H), 7.57 (d, J=8.4 Hz, 1H), 7.52-7.47 (m, 1H), 7.36 (m,1H), 7.22 (m, 1H), 7.09-6.78 (m, 4H), 3.84 (s, 3H), 3.39 (br s, 2H).

Example 92N-(2-Amino-phenyl)-4-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide(compound 144)

[0422] Step 1: 4-(1-Oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzoic acid(compound 143)

[0423] To a solution of benzene-1,2-carbaldehyde 142 (1.0 g, 7.46 mmol)in 10 mL of acetic acid was added 4-aminomethylbenzoic acid (1.13 g,7.46 mmol). The reaction mixture was refluxed 5 min and cooled to theroom temperature. A crystalline precipitate was formed and trituratedwith CH₂Cl₂ to produce the title compound 143 (1.29 g, 49%).

[0424] Step 2:N-(2-Amino-phenyl)-4-(1-oxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide(compound 144)

[0425] To a solution of the carboxylic acid (0.32 g, 0.89 mmol) in DMF(8 mL) at rt, was added HOBt (0.16 g, 1.15 mmol) and EDC (0.25 g, 1.33mmol) and the solution was stirred for 1.5 h. Lastly, phenylenediamine(0.12 g, 1.07 mmol) was added and the mixture was allowed to stir for18-20 h. DMF was removed in vacuo and the crude was partitioned betweenethyl acetate and H₂O. The organic layer was dried over Na₂SO₄ andconcentrated. Purification by column chromatography (CH₂Cl₂-MeOH (19:1))afforded 144 in 46% yield. ¹H NMR: (DMSO-d₆)

9.71 (s, 1H), 7.46 (d, J=8.0 Hz, 2H), 7.80 (d, J=8.0 Hz, 2H), 7.55-7.70(m, 3H), 7.46 (d, J=8.2 Hz, 2H), 7.20 (d, J=7.7 Hz, 1H), 7.02 (t, J=7.7Hz, 1H), 6.83 (d, J 8.0 Hz, 1H), 6.65 (t, J=7.4 Hz, 1H) 4.93 (bs, 2H),4.87 (s, 2H), 4.47 (s, 2H).

Example 94N-(2-Amino-phenyl)-4-(1,3-dioxo-1,3-dihydro-isoindol-2-ylmethyl)-benzamide(compound 149)

[0426] Phthalic anhydride 148 (1.3 g, 8.9 mmol) and 4-aminomethylbenzoicacid in 20 mL acetic acid were refluxing for 3 h, cooled to the roomtemperature and evaporated to yield a solid residue which was trituratedwith water, filtered off and dried to produce the intermediatecarboxylic acid (1.7 g, 68%). LMRS=282.0 (M+1).

[0427] Following a procedure analogous to that described in Example 92,step 2, but substituting the acid for 143, the title compound 149 wasobtained in 17% yield. ¹H NMR: (DMSO d₆)

9.59 (s, 1H), 7.82-7.91 (m, 6H), 7.40 (d, J=8.0 Hz, 2H), 7.11 (d, J=7.7Hz, 1H), 6.93 (t, J=7.7 Hz, 1H), 6.73 (d, J=8.0 Hz, 1H), 6.55 (t, J=7.4Hz, 1H), 4.83 (bs, 4H).

Example 95N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzamide(compound 152)

[0428] Step 1: 2-[2-(4-Hydroxy-phenyl)-ethyl]-isoindole-1,3-dione(compound 150)

[0429] Following a procedure analogous to that described in Example 94,step 1, but substituting 4-aminomethylbenzoic acid for tyramine thetitle compound 150 was obtained in 48% yield. LMRS=268.0 (M+1).

[0430] Step 2: 4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2:yl)ethyl)-phenyltrifluoromethane-sulfonate (151)

[0431] To a solution of sodium hydride (90 mg, 25 mmol) in dry THF (20mL) at 0° C., 150 (500 mg, 8.9 mmol) was added followed by the additionof dry DMF (2 mL). The reaction mixture was stirred for 20 min at 0° C.,treated portionwise with PhN(Tf)₂, stirred for additional 2 h andevaporated to produce a solid material which was purified bychromatography on a silica gel column, (CH₂Cl₂-MeOH (19:1)) to provide151 (639 mg, 86% yield). LMRS=400.0 (M+1).

[0432] Step 3:N-(2-Amino-phenyl)-4-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-benzamide(compound 152)

[0433] Following a procedure analogous to that described in Example 40,step 2, but substituting 151 for 42, the title compound 152 was obtainedin 15% yield. ¹H NMR: (DMSO d₆)

9.57 (s, 1H), 7.78-7.87 (m, 6H), 7.31 (d, J 8.0 Hz, 2H), 7.12 (d, J=7.7Hz, 1H), 6.93 (t, J=6.9 Hz, 1H), 6.74 (d, J=8.0 Hz, 1H), 6.56 (t, J=7.4Hz, 1H), 4.83 (bs, 2H), 3.85 (t, J=7.1 Hz, 2H), 3.00 (t, J=7.1 Hz, 2H).

Example 96N-(2-Amino-phenyl)-4-(4-oxo-4H-quinazolin-3-ylmethyl)-benzamide(compound 154)

[0434] A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol) inwater (20 mL) was treated with Et₃N (0.86 mL, 6.60 mmol) followed by theaddition of isatoic anhydride 153 (980 mg, 6.00 mmol). The reactionmixture was heated 3 h at 40° C. and evaporated to form an oily residue,which was refluxing in formic acid (20 mL) for 7 h. Formic acid wasremoved in vacuum to produce a solid, which was triturated with waterand filtered off to provide the carboxylic acid (1.61 g, 96%).LMRS=281.0 (M+1).

[0435] Following a procedure analogous to that described in Example 92,step 2, but substituting the carboxylic acid for 143, the title compound154 was obtained was obtained in 43% yield. ¹H NMR: (DMSO d₆)

9.71 (s, 1H), 8.68 (s, 1H), 8.23 (d, J=8.0 Hz, 1H), 8.01 (d, J=8.0 Hz,1H), 7.92 (t, J=8.0, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.63 (t, J=7.4, 1H),7.55 (d, J=7.7 Hz, 2H), 7.22 (d, J=7.4 Hz, 1H), 7.04 (t, J=7.1 Hz, 1H),6.85 (d, J=8.0 Hz, 1H), 6.67 (t, J=7.4 Hz, 1H), 5.35 (s, 2H).

Example 97N-(2-Amino-phenyl)-4-(4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide(compound 155)

[0436] A suspension of 4-aminomethyl benzoic acid (1.00 g, 6.60 mmol) inwater (20 mL) was treated with Et₃N (0.86 mL, 6.60 mmol) followed by theaddition of isatoic anhydride (980 mg, 6.00 mmol). The reaction mixturewas heated 3 h at 40° C. and cooled to 0° C. The cold reaction mixturewas acidified with conc. HCl (5 mL) and treated drop wise with NaNO₂solution (520 mg, 7.5 mmol in 5 mL water) over 5 min period of time,then left overnight at room temperature. A precipitate formed which wascollected, washed with water and dried to provide the carboxylic acid(1.62 g, 96%). LMRS=282.0 (M+1).

[0437] Following a procedure analogous to that described in Example 92,step 2, but substituting the carboxylic acid for 143, the title compound155 was obtained in 27% yield. ¹H NMR: (DMSO d₆)

9.62 (s, 1H), 8.25 (t, J=6.7 Hz, 2H), 8.11 (ddd, J=7.1 Hz, 1H),7.93-7.98 (m, 3H), 7.49 (d, J=8.2 Hz, 2H), 7.13 (d, J=7.7 Hz, 1H), 6.94(t, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.57 (t, J=7.7 Hz, 1H), 5.66(s, 2H), 4.87 (bs, 2H).

Example 98N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide(compound 157)

[0438] Step 1: 4-[(2-Amino-benzoylamino)-methyl]-benzoic acid (compound156)

[0439] To a suspension of 4-aminomethylbenzoic acid (5.09 g, 33.7 mmol)in H₂O (50 mL), was added Et₃N (4.7 mL, 33.7 mmol) followed by isatoicanhydride 153 (5.0 g, 30.6 mmol). The brown mixture was heated at 40° C.for 2 h until the mixture became homogeneous and then Et₃N was removedin vacuo. The resulting aqueous solution was acidified (10% HCl/H₂O) andthe mixture was partitioned between H₂O and ethyl acetate. The combinedorganic extracts were dried over Na₂SO₄, filtered and evaporated to give156 as a white solid (6.0 g, 72%). LMRS=271.0 (M+1).

[0440] Step 2:N-(2-Amino-phenyl)-4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide(compound 157)

[0441] The carboxylic acid 156 (1.72 g, 6.36 mmol) was suspended in asolution of NaOH (2.55 g, 63.6 mmol) in H₂O (12 mL). To this solutionwas added dioxane (10 mL) until mixture became homogeneous. The solutionwas cooled to 0° C. in an ice-bath and methyl chloroformate (1.25 mL,16.1 mmol) was added portionwise over 2 h. After completion of thereaction, the excess methyl chloroformate and dioxane were removed invacuo and the mixture was diluted with methanol (80 mL) and H₂O (20 mL).The solution was heated to 50° C. for 1 h. until the cyclization wascomplete. Methanol was removed in vacuo and then the aqueous layer wasextracted with ethyl acetate. Subsequently, the aqueous phase wasacidified (10% HCl/H₂O) and extracted with ethyl acetate (2×300 mL).These organic extracts were combined, dried over Na₂SO₄, filtered andevaporated to dryness. The resulting crude was triturated with warmmethanol to afford the carboxylic acid as a white solid (1.7 g, 90%).LMRS=319.0 (M+Na).

[0442] Following a procedure analogous to that described in Example 92,step 2, but substituting the quinazolinedione carboxylic acid for 143,the title compound 157 was obtained. ¹H NMR: (DMSO-d₆)

11.56 (brs, 1H), 9.59 (brs, 1H), 7.96-7.88 (m, 3H), 7.67 (dt, J=8.4, 1.4Hz, 1H), 7.30 (d, J=7.8 Hz, 2H), 7.21 (t, J=7.5 Hz, 2H), 7.13 (d, J=6.9Hz, 1H), 6.92 (dt, J=6.9, 1.2 Hz, 1H), 6.75 (d, J=6.9 Hz, 1H), 6.57 (t,J=6.9 Hz, 1H), 5.15 (brs, 2H), 4.86 (brs, 2H).

Example 99N-(2-Amino-phenyl)-4-(1-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide(compound 158)

[0443] Step 2:4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acidmethyl ester

[0444] To a solution of the quinazolinedione carboxylic acid (1.0 g,3.38 mmol) in DMF (7 mL), was added K₂CO₃ (1.4 g, 10.1 mmol) and themixture was then cooled to 0° C. Subsequently, Mel (1.05 mL, 16.9 mmol)was added and the mixture was allowed to warm to rt in the ice bathovernight. Excess methyl iodide and DMF were removed in vacuo and thecrude was partitioned between ethyl acetate and H₂O. The aqueous phasewas washed again with ethyl acetate, the combined organic extracts weredried over Na₂SO₄ and then concentrated in vacuo to yield the desiredproduct as an off-white solid (0.93 g, 85%). LMRS=325.0 (M+1).

[0445] Step 3:4-(1-Methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzoic acid

[0446] To a suspension of the methyl ester (1.25 g, 3.85 mmol) inmethanol (35 mL), was added 1N NaOH (30 mL, 38.5 mmol) and the mixturewas heated to 45-50° C. for 3 h. until it became homogeneous. Methanolwas removed in vacuo and the crude was partitioned between ethyl acetateand H₂O. The aqueous phase was acidified (10% HCl/H₂O) and extractedwith ethyl acetate (2×300 mL). These organic extracts were dried overNa₂SO₄ and concentrated in vacuo to afford product 5 as a white solid(1.15 g, 96%). LMRS=311.0 (M+1).

[0447] Step 4:N-(2-Amino-phenyl)-4-methyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide(compound 158)

[0448] Following a procedure analogous to that described in Example 92,step 2, but substituting the carboxylic acid for 143, the title compound158 was obtained in 10% yield. ¹H NMR: (DMSO-d₆) δ9.59 (brs, 1H), 8.03(d, J=7.8 Hz, 1H), 7.89 (d, J=7.8 Hz, 2H) 7.80 (dt, J=6.8, 1.5 Hz, 1H),7.49 (d, J=8.7 Hz, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.32 (t, J=7.7 Hz 1H),7.13 (d, J=7.8 Hz, 1H), 6.95 (t, J=7.6 Hz, 1H), 6.75 (d, J=7.8 Hz, 1H),6.57 (t, J=7.5 Hz 1H), 5.21 (brs, 2H), 4.86 (brs, 2H), 3.54 (s, 3H).

Example 100N-(2-Amino-phenyl)-4-(2-methyl-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide(compound 159)

[0449] A suspension of 156 (903 mg, 3.34 mmol) in acetic anhydride (15mL) was heated at 50° C. for 1 h. Acetic anhydride was evaporated undervacuum and the solid material formed was dissolved in acetic acid (30mL). This solution was refluxed 48 h and evaporated to form anothersolid material, which was recrystallized from a mixture AcOEt/CHCl₃ toproduce the intermediate carboxylic acid (420 mg, 43% yield). LMRS=385.0(M+1).

[0450] Following a procedure analogous to that described in Example 92,step 2, but substituting the carboxylic acid for 143, the title compound159 was obtained in 49% yield. ¹H NMR: (DMSO) δ(ppm): 9.64 (bs, 1H),8.17 (dd, J=8.0, 1.6 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.95 (dd, J=8.8,2.5 Hz, 1H), 7.84 (ddd, J=7.6, 7.0, 1.5 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H),7.53 (ddd, J=7.6, 7.6, 1.1 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 7.14 (dd,J=7.7, 1.1 Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J=8.0,1.4 Hz, 1H), 6.58 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 5.46 (s, 2H), 4.89 (bs,2H) 2.5 (s, 3H, overlaps with the DMSO signals).

Example 101N-(2-aminophenyl)-2-(4-Methoxy-benzylamino)-thiazol-5-yl-amide (compound163)

[0451] Step 1: 4-Methoxybenzyl-thiourea (compound 161)

[0452] To a solution of thiocarbonyl diimidazole (1.23 g, 6.22 mmol, 1.5equiv.) in dry dichloromethane (10 mL), neat alkylamine 160 (4.15 mmol,1.0 equiv.) was added dropwise at 0° C., and the solution stirred from0° C. to 15° C. during 16 h. A solution of concentrated ammoniumhydroxide (3 mL, 45 mmol, 3.6 equiv.) in 1,4-dioxane (6 mL) was added at0° C. and stirred at room temperature for 7 h. The solution was dilutedwith ethyl acetate (250 mL), washed with brine (2×50 mL), dried (MgSO₄),filtered and concentrated. After purification by column chromatography(silica gel, elution 5% methanol in dichloromethane), 161 was obtainedas yellow solid (700.2 mg,3.6 mmol, 86% yield). ¹H NMR: (Acetone-d₆)δ(ppm): 7.53 (bs, 1H), 7.28 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.8 Hz, 2H),6.67 (bs, 2H), 4.67 (s, 2H), 3.77 (s, 3H). LMRS=197.1 (M+1).

[0453] Step 2: 2-(4-Methoxybenzylamino)thiazole-5-carboxylic acid methylester (compound 162)

[0454] A solution of trans methyl-2-methoxyacrylate (461 mg, 3.97 mmol,1 equiv.) in 50% 1,4-dioxane in water (4 mL) stirred at −10° C., wastreated with N-bromosuccinimide (792 mg, 4.46 mmol, 1.12 equiv.),stirred at the same temperature for 1 h, transferred to a flaskcontaining the thiourea 161 (700.2 mg, 3.6 mmol) and the mixture wasstirred at 80° C. for 2 h. After cooling down to room temperature,concentrated NH₄OH (0.8 mL) was added, stirred for 10 min and theresulting precipitated filtered and washed with water, giving 363 mg(1.3 mmol, 36% yield) of 162, plus 454 mg additional (91% pure by HPLC)as residue from evaporation of the filtrated (ca. 77% overall yield). ¹HNMR: (Acetone-d₆) δ(ppm): 7.97 (bs, 1H), 7.72 (bs, 1H), 7.33 (d, J=8.1Hz, 2H), 6.90 (d, J=8.1 Hz, 2H), 4.52 (s, 2H), 3.78 (s, 3H), 3.75 (s,3H). LMRS=279.1 (M+1).

[0455] Step 3:N-(2-aminophenyl)-2-(4-Methoxy-benzylamino)-thiazol-5-yl-amide (compound163)

[0456] Following the procedure described in Example 1, steps 4 and 5,but substituting 162 for 6, the title compound 163 was obtained in 50%yield. ¹H-NMR (methanol-d4), δ(ppm): 7.86 (s, 1H), 7.29 (d, J=8.8 Hz,2H), 7.11 (dd, J=8.0 Hz, 1.4 Hz, 1H), 7.04 (dt, J=8.0 Hz, 1.4 Hz, 1H),6.90 (d, J=8.8 Hz, 2H), 6.86 (m, 1H), 6.74 (dt, J=7.4 Hz, 1.4 Hz, 1H),4.85 (bs, 4H), 4.45 (s, 2H), 3.78 (s, 3H).

Examples 102-121

[0457] Examples 102 to 121 describe the preparation of compounds 164 to183 using the same procedures as described for compounds 62 to 163 inExamples 47 to 101. Characterization data are presented in Tables 4a and4b. TABLE 4a Characterization of Compounds Prepared in Examples 102-121

Ex. Cpd W Y Z Name Characterization Schm 102 164

CH CH N-(2-Amino-phenyl)-4- [(3,4,5-trimethoxy- phenylamino)-methyl]-benzamide ¹H NMR: (Acetone-d₆) δ (ppm): 9.09 (bs, 1H), 7.99 (d, J=8.2Hz, 2H), 7.54 (d, J=8.0 Hz, 2H), 7.29 (d, J=7.7 Hz, 1H), 7.00 (t, J=6.6Hz, 1H), 6.86 (dd, J=8.0 Hz, 1.1 Hz, 1H), 6.67 (t, J=8.0 Hz, 1H), 5.99(s, 2H), 5.46 (bs, 1H), # 4.64 (bs, 2H), 4.43 (s, 2H), 3.69 (s, 6H),3.60 (s, 3H). 11 103 165

N CH N-(2-Amino-phenyl)-6-(3- hydoxymethyl-phenyl)- nicotinamide ¹H NMR(20% CD₃OD in CDCl₃) δ (ppm): 9.14 (d, J=1.8 Hz, 1H), 8.33(dd, J=8.4 Hz,1.8 Hz, 1H), 7.93 (s, 1H), 7.82 (m, 2H), 7.50-7.40 (m, 2H), 7.22-6.45(m, 4H), 4.69 (s, 2H). 15 104 166

CH CH N-(2-Amino-phenyl)-4-(3- methoxy-phenyl)- benzamide ¹H NMR (CD₃OD)δ (ppm): 7.98 (d, J=8.4 Hz, 2H), 7.65 (d, J=8.4 Hz, 2H), 7.31-7.04 (m,5H), 6.92-6.80 (m, 3H), 3.84 (s, 3H). 15 105 167

CH N N-(2-amino-phenyl)-6-(4- methoxy-benzylamino)- nicotinamide ¹H NMR(DMSO-d₆) δ (ppm): 9.33 (s, 1H), # 8.61 (d, J=2.5 Hz, 1H), 7.89 (dd,J=8.8 Hz, 2.2 Hz, 1H), 7.57 (t, J=5.8 Hz, 1H), 7.24 (d, J=8.52 Hz, 2H),7.11 (d, J=7.69 Hz, 1H), 6.90 (m, 3H), 6.73 (d, J=8.0 Hz, 1H), 6.50-6.58(m, 2H), 4.83 (s, 2H), 4.45 (d, J=5.8 Hz, 2H), 3.70 (s, 3H). 6 106 168

CH N N-(2-amino-phenyl)-6-[2-(4- methoxy-phenyl)-ethylamino]-nicotinamide ¹H NMR (DMSO-d₆) δ (ppm): 9.42 (s, 1H), 8.72(d, J=2.5 Hz, 1H), 7.97 (dd, J=8.8 Hz, 2.5 Hz, 1H), 7.23 (m, 4H),6.81-7.03 (m, 4H), 6.64 (m, 1H), 6.56 (d, # J=9.1 Hz, 1H), 4.92 (s, 2H),3.78 (s, 3H), 3.55 (m, 2H), 2.85 (t, J=7.3 Hz, 2H). 6 107 169

CH CH N-(2-Amino-phenyl)-4-[(4,6- dimethoxy-pyrimidin-2-ylamino)-methyl]- benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.63 (bs, 1H),7.95 (d, J=7.9 Hz, 2H), 7.85-7.82 (m, 1H), # 7.48 (d, J=7.9 Hz, 2H),7.20 (d, J=7.1 Hz, 1H), 7.03 (dt, J=7.6 Hz, 7.4 Hz, 1H), 6.81 (d, J=7.9Hz, 1H), 6.63 (dt, J=7.9 Hz, 7.7 Hz, 1H), 4.94 (bs, 2H), 4.54 (d, J=6.0Hz, 2H), 3.79 (bs, 6H). 11 108 170

CH CH N-(2-Amino-phenyl)-4- (quinolin-2- ylsulfanylmethyl)-benzamide ¹HNMR: (DMSO-d₆) δ (ppm): 9.62 (bs, 1H), 8.21 (d, J=8.8 Hz, 1H), 8.00-7.89(m, 4H), 7.79 (dd, J=6.8 # Hz, 1.3 Hz, 1H), 7.68 (d, J=6.3 Hz, 2H), 7.56(t, J=6.8 Hz, 1H), 7.44 (d, J=8.7 Hz, 1H), 7.17 (d, J=8.2 Hz, 1H), 6.99(dt, J=7.9 Hz, 7.4 Hz, 1H), 6.79 (d, J=6.9 Hz, 1H), 6.61 (dt, J=7.7 Hz,7.4 Hz, 1H), 4.69 (s, 2H). 11 109 171

N CH N-(2-Amino-phenyl)-6-(4- methoxy-benzylsulfanyl)- nicotinamide ¹HNMR: (DMSO-d₆) δ (ppm): 9.06 (bs, 1H), 8.17 (dt, J=10.9 Hz, 9.0 Hz, 1H),7.46 (d, J=8.5 Hz, # 1H), 7.39 (d, J=8.2 Hz, 2H), 7.21-7.13 (m, 2H),7.01 (dt, J=7.6 Hz, 7.4 Hz, 1H), 6.91 (d, J=8.5 Hz, 2H), 6.80 (d, J=7.9Hz, 1H), 6.62 (t, J=7.4 Hz, 1H), 5.01 (bs, 2H), 4.47 (s, 2H), 3.76 (s,3H). 12 110 172

CH CH N-(2-Amino-phenyl)-4- (benzothiazol-2- ylsulfanylmethyl]-benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 8.01 (d, J=8.0 Hz, 1H), 1.93 (d,J=8.2 Hz, 2H), 7.90 (dd, J=4.4 Hz, # 0.6 Hz, 1H), 7.63 (d, J=8.2 Hz,2H), 7.48 (dt, J=8.0 Hz, 0.8 Hz, 1H), 7.37 (td, J=7.1 Hz, 1.1 Hz, 1H),7.14 (d, J=7.1 Hz, 1H), 6.96 (t, J=6.3 Hz, 1H), 6.76 (d, J=7.7 Hz, 1H),6.58 (t, J=6.6 Hz, 1H), 4.88 (s, 2H), 4.73 (s, 2H). 11 112 174

CH N N-(2-amino-phenyl)-6-[2-(4- fluoro-phenyl)-ethylamino]-nicotinamide ¹H NMR (DMSO-d₆) δ (ppm): 9.34 (s, 1H), 8.64 (d, J=2.5 Hz,1H), 7.89 (dd, # J=9 Hz, 2 Hz, 1H), 7.16-7.22 (m, 3H), 7.06-7.20 (m,3H), 6.90-6.96 (m, 1H), 6.72-6.78 (m, 1H), 6.46-6.60 (m, 2H), 4.92 (s,2H), 3.50 (m, 2H), 2.92 (m, 2H). 6 113 175

CH N N-(2-amino-phenyl)-6-(4- fluoro-benzylamino)- nicotinamide ¹H NMR(DMSO-d₆) δ (ppm): 9.34 (s, 1H), 8.61 (d, J=2.2 Hz, 1H), 7.91 (dd, J=8.8Hz, # 2.2 Hz, 1H), 7.66 (t, J=6 Hz, 1H), 7.32-7.37 (m, 2H), 7.08-7.38(m, 3H), 6.93 (m, 1H), 6.74 (m, 1H), 6.52-6.58 (m, 2H), 4.84 (s, 2H),4.51 (d, J=6.0 Hz) 6 114 176

CH N N-(2-amino-phenyl)-6- (3,4,5-trimethoxy- benzylamino)-nicotinamide¹H NMR (DMSO-d₆) δ (ppm): 9.34 (s, 1H), 8.63 (d, J=2.2 Hz, 1H), 7.92(dd, J=8.8 Hz, # 2.2 Hz, 1H), 7.57 (t, J=6 Hz, 1H), 7.10 (m, 1H), 6.93(m, 1H), 6.74 (m, 1H), 6.66 (s, 2H), 6.56 (m, 2H), 4.84 (s, 2H), 4.45(d, J=6 Hz, 2H), 3.73 (s, 6H), 3.31 (s, 3H). 6 115 177

CH CH N-(2-Amino-phenyl)-4-(5- phenyl-[1,3,4]oxadiazol-2-ylsulfanylmethyl]- benzamide ¹H NMR: (Acetone-d₆) δ (ppm): 9.08 (bs,1H), 8.02 (dd, J=7.1 Hz, 1.9 Hz, # 4H), 7.69 (d, J=8.5 Hz, 2H),7.62-7.57 (m, 3H), 7.28 (d, J=7.7 Hz, 1H), 7.03-6.97 (m, 1H), 6.86 (d,J=6.6 Hz, 1H), 6.67 (t, J=7.7 Hz, 1H), 4.70 (s, 2H), 4.63 (bs, 2H). 14116 178

N CH N-(2-aminophenyl)-6-(2- phenylamino-ethylamino)- nicotinamide¹H-NMR (CD₃OD-d4), δ (ppm): 8.67 (d, J=2.2 Hz, 1H), 7.97 (dd, J=8.9 Hz,2.5 Hz, 1H), 7.58 (m, 1H), 7.51 (m, 1H), 7.15 (dd, # J=7.7 Hz, 1.1 Hz,1H), 7.08 (m, 2H), 6.89 (dd, J=8.0 Hz, 1.4 Hz, 1H), 6.76 (dt, J=7.7 Hz,4.4 Hz, 1H), 6.67 (t, J=7.7 Hz, 2H), 6.60 (m, 2H), 4.87 (bs, 4H), 3.60(t, J=6.3 Hz, 2H), 3.35 (t, J=6.3 Hz, 2H). 11 117 179

CH CH N-(2-Amino-phenyl)-4-(2,4- ¹H NMR: (DMSO-d₆) δ (ppm): 9.62 (s,1H), 8.00 (dd, J=8.2 Hz, 1.9 Hz, 1H), 7.80-7.92 (m, 3H), 7.42-7.50 # (m,4H), 7.13 (d, J=7.1 Hz, 1H), 6.95 (ddd, J=8.0 Hz, 1.6 Hz, 1H), 6.75 (dd,J=8.0 Hz, 1.4 Hz, 1H), 6.57 (t, J=7.7 Hz, 1H), 5.13 (s, 2H), 4.87 (bs,2H). 11 118 180

CH CH N-(2-Amino-phenyl)-4-(4- ethyl-4-methyl-2,6-dioxo-piperidin-1-ylmethyl)- benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.59 (s,1H), 7.88 (d, J=8.2 Hz, 2H), 7.31 (d, J=8.2 Hz, 2H), # 7.13 (d, J=7.4Hz, 1H), 6.95 (t, J=8.0 Hz, 1H), 6.75 (d, J=8.0 Hz, 1H), 6.57 (t, J=7.4Hz, 1H), 4.87 (s, 2H), 4.86 (bs, 2H), 2.61 (s, 2H), 2.55 (s, 2H), 1.31(q, J=7.7 Hz, 2H), 0.91 (s, 3H), 0.80 (t, J=7.4 Hz, 3H). 11 119 181

CH CH N-(2-Amino-phenyl)-4-(1- ethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3- ylmethyl)-benzamide ¹H NMR: (CDCl₃) δ (ppm):8.23 (dd, J=7.8 Hz, 1.5 Hz, 1H), 8.01 (bs, 1H), 7.80 (d, # J=8.0 Hz,2H), 7.71-7.65 (m, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.27-7.20 (m, 3H), 7.05(dt, J=7.7, 1.5 Hz, 1H), 6.81-6.77 (m, 2H), 5.29 (bs, 2H), 4.18 (q,J=7.3 Hz, 2H), 3.86 (bs, 2H), 1.33 (t, J=7.1 Hz, 3H). 19 120 182

CH CH N-(2-Amino-phenyl)-4-(4,6- dimethyl-pyrimidin-2-ylsulfanylmethyl)- benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.66 (bs, 1H), #7.96 (d, J=7.9 Hz, 2H), 7.61 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 1H),7.04-6.99 (m, 2H), 6.82 (d, J=7.9 Hz, 1H), 6.64 (t, J=7.4 Hz, 1H), 4.49(s, 2H), 2.42 (s, 6H). 11 121 183

CH CH N(2-Amino-phenyl)-4-(4- trifluoromethyl-pyrimidin-2-ylsulfanylmethyl)benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.66 (bs, 1H),9.07 (d, J=5.2 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 7.78 # (d, J=4.7 Hz,1H), 7.63 (d, J=7.4 Hz, 2H), 7.19 (d, J=7.7 Hz, 1H), 7.01 (dt, J=7.7 Hz,7.4 Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.64 (dt, J=7.4 Hz, 7.1 Hz, 1H),4.94 (bs, 2H), 4.57 (s, 2H). 11

[0458] TABLE 4b

Ex. Cpd W Y Z Name Characterization Schm 123 187

CH CH N-(2-Aminophenyl)- 4-[3-(pyridin-2ylmethyl-aminomethyl)phenyl)]-benzamide ¹H NMR (20% CD₃OD in CDCl₃) δ (ppm): 8.46(m, 1H), 7.95 (d, J=8.4 Hz, 2H), 7.64-6.70 (m, 14 H), 3.80 (br s, 4H).21 124 188

CH CH Biphenyl-4,4′-dicarboxylic acid bis-[(2-amino-phenyl)-amide] ¹HNMR (CD₃OD) δ (ppm): 9.80 (bs, 2H), 8.16 # (d, J=7.9 Hz, 4H), 7.96 (d,J=7.9 Hz, 4H), 7.23 (d, J=7.4 Hz, 2H), 7.03 (dd, J=6.9, 7.4 Hz, 2H),6.84 (d, J=8.2 Hz, 2H), 6.66 (dd, J=6.9, 7.7 Hz, 2H), 5.06 (bs, 4H).  1125 189

CH CH N-(2-Amino-phenyl)-4-[4-{(3,4,5- trimethoxy-phenylamino)-methyl}-phenyl]-benzamide ¹H NMR (DMSO-d₆) δ (ppm): 10.15 (1H, brs),8.17 (2H, d, J=8.0), 7.90 (2H, d, J=8.2), # 7.87 (1H, brs), 7.72 (1H, d,J=6.6), 7.54 (2H, m), 7.40 (1H, d, J=8.5), 7.25 (1H, m), 7.16 (1H, d,J=7.4), 7.07 (1H, m), 6.08 (2H, s), 4.42 (2H, s), 3.73 (6H, s), 3.58(3H, d, J=0.8) 21 126 190

CH CH N-(2-Amino-phenyl)- 4-[4-{(4-methoxy-phenylamino)-methyl}-phenyl]-benzamide 1H NMR (DMSO-d₆) δ (ppm): 10.03 (lH, brs),8.17 (2H, d, J=7.7), 7.88 (3H, m), # 7.76(1H, d, J=7.1), 7.52 (2H, m),7.35 (1H, d, J=8.0), 7.17 (1H, m), 7.08-6.93 (6H, m), 4.50 (3H, s), 3.75(2H, s) 21 128 193

CH CH N-(2-Amino-phenyl)- 4-(3-methyl-but-3- en-1-ynyl)-benzamide LRMScalc: 276.03, found: 277.2 (MH)⁺ 22 129 194

CH CH N-(2-Amino-phenyl)-4-(1-hydroxy- cyclohexylethynyl)-benzamide LRMScalc: 334.4, found: 335 (MH)⁺ 22 130 195

CH CH N-(2-Amino-phenyl)- 4-(3-hydroxy-3- methyl-but-1-ynyl)-benzamideLRMS calc: 294.35, found: 295.1 (MH)⁺ 22 131 196

CH CH N-(2-Amino-phenyl)- 4-phenylethynyl-benzamide LRMS calc: 312.37,found: 313.2 (MH)⁺ 22 180 320

CH CH N-(2-Amino-phenyl)- 4-[(5-chloro-benzooxazol-2-ylamino)-methyl]-benzamide ¹H NMR: (Acetone-d₆) δ (ppm): 9.67 (s, 1H),8.85 (s, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, # 2H), 7.45 (d,J=8.8 Hz, 1H), 7.36 (d, J=2.3 Hz, 1H), 7.22 (d, J=7.6 Hz, 1H), 7.07 (dd,J=8.8, 2.3 Hz, 1H), 7.02 (d, J=7.0 Hz, 1H), 6.84 (d, J=7.6 Hz, 1H), 6.65(t, 7.0 Hz, 1H), 4.94 (s, 2H), 4.67 (d, J=5.3 Hz 2H). 35 181 321

CH CH N-(2-Amino-phenyl)- 4{[4-(4-Chloro-phenyl)-thiazol-2-ylamino]-methyl}-benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.67 (bs, 1H),8.36 (t, J=5.8 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.89 # (d, J=8.2 Hz,2H), 7.57 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.2 Hz, 2H), 7.20 (s, 1H), 7.02(t, J=8.5 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 6.65 (t, J=7.1 Hz, 1H), 4.92(bs, 2H), 4.65 (d, J=5.8 Hz, 2H). 35 182 322

CH CH N-(2-Amino-phenyl)-4-[(5-bromo- benzothiazol-2-ylamino)-methyl]-benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 6.97 (s, 1H), 8.78(bs, 1H), 8.01 (d, J=8.8 Hz, 2H), 8.00 (s, 1H), 7.55 (d, # J=8.2 Hz,2H), 7.43-7.35 (m, 2H), 7.22 (d, J=7.6 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H),6.83 (d, J=7.6 Hz, 1H), 6.65 (t, J=7.6 Hz, 1H), 4.94 (s, 2H), 7.74 (d,J=5.9 Hz, 2H). 33, 34 183 323

CH CH N-(2-Amino-phenyl)-4-{5-[(3,4,5- trimethoxy-phenylamino)-methyl]-thiophen-2- ylmethyl}-benzamide LRMS calc: 489.58, found: 490(MH)⁺ 21 184 325

CH CH N-(2-Amino-phenyl)-4-{6- [(pyridin-3-ylmethyl)-amino]-benzothiazol-2-ylsulfanylmethyl}- benzamide ¹H NMR: (Acetone-d₆) δ(ppm): 8.65 (d, J=1.4 Hz, 1H), 8.44 (dd, # J=4.7, 3.0 Hz, 1H), 7.97 (d,J=8.2 Hz, 2H), 7.81-7.77 (m, 1H), 7.63 (m, 3H), 7.33-7.26 (m, 2H), 7.09(d, J=2.5 Hz, 1H), 7.02-6.97 (m, 1H), 6.91 (dd, J=8.8, 2.5 Hz, 1H), 6.86(dd, J=8.0, 1.4 Hz, 1H), 6.69-6.64 (m, 1H), 4.64 (s, 2H), 4.47 (s, 2H).11 185 326

CH CH N-(2-Amino-phenyl)-4-{6- [(pyridin-2-ylmethyl)-amino]-benzothiazol-2-ylsulfanylmethyl}- benzamide ¹H NMR: (DMSO-d₆) δ (ppm):9.59 (s, 1H), 8.52-8.51 (m, 1H), 7.89 (d, J=8.24 Hz, 2H), 7.71 (td,J=7.7, # 1.9 Hz, 1H), 7.59-7.53 (m, 3H), 7.34 (d, J=8.0 Hz, 1H),7.25-7.21 (m, 1H), 7.12 (d, J=6.9, Hz, 1H), 6.98-6.96 (m, 1H), 6.93 (d,J=7.4 Hz, 1H), 6.81 (dd, J=9.1, 2.5 Hz, 1H), 6.76-6.73 (m, 1H), 6.67 (t,J=5.8 Hz, 1H), 6.56 (t, J=7.4 Hz, 1H), 4.87 (s, 1H), 4.58 (s, 2H), 4.38(d, J=6.3 Hz, 2H). 11, 34 186 327

CH CH N-(2-Amino-phenyl)-4-(1H- imidazo-2-ylsulfanylmethyl)- benzamide¹H NMR: (DMSO-d₆) δ (ppm): 12.23 (bs, 1H), 9.59 # (s, 1H), 7.86 (d,J=8.2 Hz, 2H), 7.34 (d, J=8.5 Hz, 2H), 7.14-7.12 (m, 2H), 6.94-6.92 (m,2H), 6.76 (d, J=6.6 Hz, 1H), 6.57 (t, J=7.4 Hz, 1H), 4.87 (s, 2H), 4.29(s, 2H). 14 187 328

CH CH N-(2-Amino-phenyl)-4-morpholin- 4-ylmethyl-benzamide ¹H NMR:(CD₃OD) δ (ppm): 8.03 (d, J=8.4 Hz, 2H), 7.58 (d, J=7.9 Hz, 2H), 7.26(d, # J=7.0 Hz, 1H), 7.16 (t, J=6.6 Hz, 1H), 6.98 (d, J=7.0 Hz, 1H),6.85 (t, J=7.5 Hz, 1H), 3.78 (t, J=4.4 Hz, 4H), 3.68 (s, 2H), 2.57-2.54(m, 4H). 37 188 329

CH CH 3′,4′,5′-Trimethoxy- biphenyl-4-carboxylic acid (2-amino-phenyl)-amide ¹H NMR: (CD₃OD) δ (ppm): 8.14 (d, J=7.9 Hz, # 2H),7.85 (d, J=8.4 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 7.17 (t, J=7.0 Hz, 1H),7.04 (s, 2H), 7.00 (d, J=8.4 Hz, 1H), 6.87 (t, J=7.5Hz, 1H), 4.95 (s,6H), 4.01 (s, 3H). 37 189 330

CH CH 4-[(2-Amino-9-butyl- 9H-purin-6-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 9.65 (s, 1H),7.96 (d, J=7.7 Hz, 2H), 7.95 (bs, 2H) 7.78 (s, 1H), 7.52 (d, # J=7.9 Hz,2H), 7.22 (d, J=7.7 Hz, 1H), 7.02 (dd, J=7.3, 8.0 Hz, 1H), 6.8 (d, J=8.0Hz, 1H), 6.65 (dd, J=7.3, 7.7 Hz, 1H), 5.91 (s, 2H), 4.94 (bs, 2H), 4.77(bs, 2H), 4.01 (t, J=7.1 Hz, 1H), 1.78 (m, 2H), 1.3 (m, 2H), 0.95 (t,J=7.4, Hz, 1H) 39 190 331

CH CH N-(2-Amino-phenyl)-4-[(2-amino- 9H-purin-6-ylamino)-methyl]-benzamide ¹H NMR (DMSO-d₆) δ (ppm): 10.16 (s, 1H), 9.60 # (br,1H), 8.24 (s, 1H), 8.08 (d, J=8.0 Hz, 2H), 7.62 (m, 1H), 7.60 (d, J=8.0Hz, 2H), 7.40 (m, 1H), 7.20 (m, 2H), 7.08 (m, 1H), 4.90 (m, 2H), 4.6(br, 4H) 39 191 332

CH CH N-(2-Amino-phenyl)-4-[(2-chloro- 9H-purin-6-ylamino)-methyl]-benzamide ¹H NMR (DMSO-d₆) δ (ppm): 9.67 (m, 1H), 8.80 (m, 1H), 8.24 (s,1H), 7.99 # (d, J=7.8 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.8Hz, 1H), 7,02 (dd, J=6.3, 7.8 Hz, 1H), 6.82 (d, J=8.1 Hz, 1H), 6.70 (d6,J=6.3, 8.1 Hz, 1H), 4.94 (br, 2H), 4.77 (br, 2H) 39 192 333

CH CH N-(2-Amino-phenyl)-4-[(9-butyl- 2-chloro-9H-purin-6-ylamino)-methyl]-benzamide ¹H NMR (DMSO-d₆) δ (ppm): 9.60 (s, 1H), 8.72 (br, 1H),8.21 (s, 1H), 7.92 (d, # J=8.0 Hz, 2H), 7.45 (d, J=8.0 Hz, 2H), 7.15 (d,J=8.0 Hz, 1H), 6.96 (dd, J=6.7, 8.0 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H),6.58 (dd, J=6.7, 8.0 Hz, 2H), 4.88 (s, 1H), 4.71 (m, 2H), 4.11 (m, 2H),1.76 (m, 2H), 1.25 (m, 2H), 0.89 (t, J=7.1 Hz, 3H) 39 193 334

CH CH N-(2-Amino-phenyl)-4-[(1H- benzoimidazol-2-ylmethyl)-amino]-benzamide ¹H NMR: (DMSO-d₆) δ (ppm): 12.39 (bs, 1H), 9.32 (s,1H), 7.81 (d, J=8.2 Hz, 2H), 7.56 (bs, 1H), # 7.21-7.17 (m, 3H),6.99-6.97 (m, 2H), 6.81 (d, J=8.2 Hz, 1H), 6.77 (d, J=8.8 Hz, 2H), 6.63(t, J=7.0 Hz, 1H), 4.85 (s, 2H), 4.62 (d, J=5.3 Hz, 2H). 11 194 335

CH CH N-(2-Amino-phenyl)-4-(1-ethyl- 2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (CDCl₃) δ (ppm): 8.23 (dd,J=7.8, 1.5 Hz, 1H), 8.01 (bs, 1H), 7.80 (d, J=8.0 Hz, 2H), # 7.71-7.65(m, 1H), 7.55 (d, J=8.2 Hz, 2H), 7.27-7.20 (m, 3H), 7.05 (td, J=7.7, 1.5Hz, 1H), 6.81-6.77 (m, 2H), 5.29 (bs, 2H), 4.18 (q, J=7.3 Hz, 2H), 3.86(bs, 2H), 1.33 (t, J=7.1 Hz, 3H). MS: (calc.) 414.2; (obt.) 415.3 (MH)⁺19 195 336

CH CH N-(2-Amino-phenyl)-4-(6-chloro- 2-methyl-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.69 (bs, 1H, NH), 8.71 (s,1H), 8.16 (d, J=2.5 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.95 (dd, J=8.8,2.5 Hz, 1H), 7.81 # (d, J=8.8 Hz, 1H), 7.74 (d, J=8.2 Hz, 2H), 7.20 (d,J=7.1 Hz, 1H), 7.02 (td, J=7.6, 1.5 Hz, 1H), 6.82 (dd, J=8.0, 1.4 Hz,1H), 6.64 (td, J=7.6, 1.4 Hz, 1H), 5.34 (s, 2H), 4.94 (bs, 2H). MS:(calc.) 404.1; (obt.) 405.0 (MH)⁺ 19 196 337

CH CH N-(2-Amino-phenyl)-4-(2-methyl- 4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.64 (bs, 1H), 8.17 (dd,J=8.0, 1.6 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H), 7.95 (dd, J=8.8, 2.5 Hz,1H), 7.84 (ddd, J=7.6, 7.0, # 1.5 Hz, 1H), 7.64 (d, J=7.7 Hz, 1H), 7.53(ddd, J=7.6, 7.6, 1.1 Hz, 1H), 7.33 (d, J=8.2 Hz, 2H), 7.14 (dd, J=7.7,1.1 Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, # J=8.0, 1.4Hz, 1H), 6.58 (ddd, J=7.6, 7.6, 1.3 Hz, 1H), 5.46 (s, 2H), 4.89 (bs, 2H)2.5 (s, 3H). MS: (calc.) 384.2; (obt.) 385.0 (MH)⁺ 19 197 338

CH CH N-(2-Amino-phenyl)-4-(6,7- dimethoxy-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.62 (bs, 1H), 8.50 (s,1H), 8.41 (d, J=8.2 Hz, 2H), 7.47 (s, 1H), 7.46 (d, J=7.7 Hz, 2H), 7.17(s, 1H), 7.15 (d, # J=8.5 Hz, 1H), 6.96 (ddd, J=7.7, 7.7, 1.1 Hz, 1H),6.76 (d, J=6.9 Hz, 1H), 6.58 (dd, J=6.9, 6.9 Hz, 1H), 5.26 (s, 2H), 4.88(bs, 2H), 3.91 (s, 3H), 3.87 (s, 3H). MS: (calc.) 430.2; (obt.) 431.1(MH)⁺ 19 198 339

CH CH N-(2-Amino-phenyl)-4-(6,7- difluoro-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.66 (bs, 1H), 8.69 (s, 1H),8.07 (dd, J=8.8, 10.4 Hz, 1H), 7.96 (d, J=8.2 Hz, 2H), 7.82 (dd, J=14.3,11.3 Hz, 1H), 7.48 # (d, J=8.2 Hz, 2H), 7.15 (d, J=6.9 Hz, 1H), 6.96(ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.76 (dd, J=8.1, 1.2 Hz, 1), 6.58 (ddd,J=7.5, 7.5, 1.2 Hz, 1H), 5.28 (s, 2H), 4.89 (bs, 2H). MS: (calc.) 406.1;(obt.) 407.0 (MH)⁺ 19 199 340

CH CH N-(2-Amino-phenyl)-4-[1-(2- dimethylamino-ethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3- ylmethyl]-benzamide ¹H NMR: (DMSO) δ (ppm):9.61 (bs, 1H), 8.09 (dd, J=7.8, 1.5 Hz, 1H), 7.91 (d, J=8.2 Hz, 2H),7.81 (ddd, J=7.8, 7.8, 1.6 Hz, 1H), 7.52 (d, J=8.2 Hz, # 1H), 7.42 (d,J=8.2 Hz, 2H), 7.32 (dd, J=7.6, 7.6 Hz, 1H), 7.14 (d, J=6.9 Hz, 1H),6.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J=7.8, 1.2 Hz, 1H), 6.59(ddd, J=7.5, 7.5, 1.2 Hz, 1H), 5.22 (s, 2H), 4.88 (bs, 2H), 4.24 (t,J=7.1 Hz, 2H), 2.5 (m, 2H) 2.22 (s, 6H). MS: (calc.) 457.2; (obt.) 458.1(MH)⁺ 19 200 341

CH CH N-(2-Amino-phenyl)-4-[1-(2- morpholin-4-yl-ethyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3- ylmethyl]-benzamide ¹H NMR: (DMSO) δ (ppm):9.61 (bs, 1H), 8.09 (dd, J=8.0, 1.6 Hz, 1H), 7.92 (d, J=8.2 Hz, 2H),7.81 (ddd, J=7.8, 7.8, 1.6 Hz, 1H), 7.54 (d, J=8.5 Hz, 1H), 7.43 (d,J=8.2 # Hz, 2H), 7.32 (dd, J=7.4, 7.4 Hz, 1H), 7.14 (d, J=7.4 Hz, 1H),6.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J=8.0, 1.4 Hz, 1H), 6.59(ddd, J=7.6, 7.6, 1.4 Hz, 1H), 5.22 (s, 2H), 4.87 (bs, 2H), 4.28 (t,J=6.7 Hz, 2H), 3.50 (t, J=4.5 Hz, 4H), 2.58 (t, J=6.7 Hz, 2H), 2.47-2.44(m, 4H). MS: (calc.) 499.2; (obt.) 500.3 (MH)⁺. 19 201 342

CH CH N-(2-Amino-phenyl)-4-(6-bromo- 2-methyl-4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.65 (bs, 1H), 8.25 (d,J=2.5 Hz, 1H), 7.99 (ddd, J=8.5, 2.5, 0.8 Hz, 1H), 7.95 (d, J=8.8 Hz,2H), 7.60 (d, J=8.8 Hz, 1H), 7.34 (d, J=8.2 # Hz, 2H), 7.14 (d, J=7.4Hz, 1H), 6.96 (dd, J=7.4, 7.4 Hz, 1H), 6.76 (d, J=8.0 Hz, 1H), 6.59 (dd,J=7.4, 7.4 Hz, 1H), 5.45 (s, 2H), 4.88 (bs, 2H). MS: (calc.) 462.1;(obt.) 463.1 (MH)⁺. 19 202 343

CH CH N-(2-Amino-phenyl)-4-(2,4-dioxo- 1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3- ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.61 (bs,1H), 8.10 (dd, J=5.2, 0.5 Hz, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.40 (d,J=8.2 Hz, 2H), 7.15 (d, J=7.1 Hz, 1H), # 6.98-6.94 (m, 2H), 6.77 (dd,J=8.0, 1.1 Hz, 1H), 6.58 (dd, J=7.1, 7.1 Hz, 1H), 5.12 (s, 2H), 4.88(bs, 2H). MS: (calc.) 392.1; (obt.) 393.0 (MH)⁺. 43 203 344

CH CH N-(2-Amino-phenyl)-4-(6-bromo- 1-ethyl-2,4-dioxo-1,4-dihydro-2H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H),8.15 (d, J=2.5 Hz, 1H), 7.95 (dd, J=9.1, 4.9 Hz, 1H), 7.91 (d, J=8.2 Hz,2H), 7.53 (d, J=9.3 Hz, 1H), 7.42 (d, # J=8.2 Hz, 2H), 7.15 (d, J=6.9Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J=8.1, 1.5 Hz,1H), 6.59 (ddd, J=7.6, 7.6, 1.4 Hz, 1H), 5.20 (s, 2H), 4.88 (bs, 2H)4.14 (q, J=7.0, 2H), 1.21 (t, J=7.0, 3H). MS: (calc.) 492.1; (obt.)493.0 (MH)⁺. 19 204 345

CH CH N-(2-Amino-phenyl)-4-[1-(4- methoxy-benzyl)-2,4-dioxo-1,4-dihydro-2H-quinazolin-3- ylmethyl]-benzamide ¹H NMR: (DMSO) δ (ppm):9.62 (bs, 1H), 8.10 (dd, J=7.7, 1.6 Hz, 1H), 7.93 (d, J=8.2 Hz, 2H),7.71 (ddd, J=7.9, 7.9, 1.5 Hz, 1H), 7.46 (d, J=8.2 Hz, 2H), # 7.38 (d,J=8.2 Hz, 2H), 7.31 (d, J=7.4 Hz, 1H), 7.26 (d, J=8.8 Hz, 2H), 7.15 (d,J=6.6 Hz, 1H), 6.96 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 6.89 (d, J=8.8 Hz,2H), # 6.77 (dd, J=8.0, 1.4 Hz, 1H), 6.59 (ddd, J=7.5, 7.5, 1.2 Hz, 1H),5.33 (s, 2H), 5.28 (s, 2H), 4.89 (bs, 2H), 3.71 (s, 3H). MS: (calc.)506.2; (obt.) 507.1 (MH)⁺. 19 205 346

CH CH N-(2-Amino-phenyl)-4-(6-bromo- 4-oxo-4H-quinazolin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.61 (bs, 1H), 8.66 (s, 1H), 8.24 (d,J=2.5 Hz, 1H), 8.00 (dd, J=8.7, 2.3 Hz, 1H), 7.95 (d, J=8.2 Hz, 2H),7.68 (d, J=8.8 Hz, # 1H), 7.48 (d, J=8.2 Hz, 2H), 7.15 (d, J=8.0 Hz,1H), 7.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J=8.0, 1.1 Hz, 1H),6.59 (dd, J=7.4, 7.4 Hz, 1H), 5.28 (s, 2H), 4.87 (bs, 2H). MS: (calc.)448.0; (obt.) 449.0 (MH)⁺. 19 206 347

CH CH N-(2-Amino-phenyl)-4-(6-bromo- 4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.63 (bs, 1H), 8.38 (d,J=1.9 Hz, 1H), 8.28 (dd, J=8.8, 2.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H),7.95 (d, J=8.0 Hz, # 2H), 7.50 (d, J=8.2 Hz, 2H), 7.15 (d, J=6.9 Hz,1H), 7.96 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.77 (dd, J=8.0, 1.4 Hz, 1H),6.59 (ddd, J=7.6, 7.6, 1.4 Hz, 1H), 5.67 (s, 2H), 4.87 (bs, 2H). MS:(calc.) 449.0; (obt.) 450.0 (MH)⁺. 19 207 348

CH CH N-(2-Amino-phenyl)-4-(6-chloro- 4-oxo-4H-benzo[d][1,2,3]triazin-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.63 (bs, 1H), 8.30-8.24(m, 2H), 8.15 (ddd, J=8.6, 2.5, 0.8 Hz, 1H), 7.95 (d, J=8.0 Hz, 2H),7.50 (d, J=8.2 Hz, 2HH), # 7.15 (d, J=8.0 Hz, 1H), 7.96 (dd, J=7.4, 7.4Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.59 (dd, J=7.4, 7.4 Hz, 1H), 5.67 (s,2H), 4.88 (bs, 2H). MS: (calc.) 405.1; (obt.) 406.0 (MH)⁺. 19 208 349

CH CH N-(2-Amino-phenyl)-4-[(3-fluoro- 2-pyridinyl-amino)-methyl]-benzamide ¹H NMR (acetone-d₆) δ (ppm): 9.07 (bs, 1H), 8.02 (d, J=8.2 Hz,2H), 7.64-7.44 (m, 3H), 7.33 (dd, J=7.8, 1.5 Hz, 1H), 7.03 (td, J=7.6,1.5 Hz, 1H), # 6.90 (dd, J=8.0, 1.4 Hz, 1H), 6.78 (bs, 1H), 6.71 (td,J=7.6, 1.4 Hz, 1H), 6.48 (dd, J=8.1, 2.6 Hz, 1H), 6.16 (dd, J=7.7, 2.5Hz, 1H), 4.76-4.55 (m, 4H). HRMS (calc.): 336.1386, (found): 336.1389.11 209 350

CH CH N-(2-Amino-phenyl)-4-[(3,4,5- trifluoro-2-pyridinyl-amino)-methyl]-benzamide ¹H NMR (acetone-d₆) δ (ppm): 9.06 (bs, 1H), AB system(δ_(A)=8.02, δ_(B)=7.56, J=8.3 Hz, 4H), # 7.74-7.65 (m, 1H), 7.33 (d,J=8.0, 1H), 7.03 (td, J=7.6, 1.5 Hz, 1H), 6.96-6.83 (m, 2H), 6.71 (td,J=7.6, 1.4 Hz, 1H), 4.74 (d, J=6.3 Hz, 2H), 4.65 (bs, 2H). 11 210 351

CH CH N-(2-Amino-phenyl)-4-(2,4-dioxo- 1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl)- benzamide ¹H NMR: (DMSO) δ (ppm): 9.61 (bs,1H), 8.10 (dd, J=5.2, 0.5 Hz, 1H), 7.91 (d, J=8.2 Hz, 2H), 7.40 (d, #J=8.2 Hz, 2H), 7.15 (d, J=7.1 Hz, 1H), 6.98-6.94 (m, 2H), 6.77 (dd,J=8.0, 1.1 Hz, 1H), 6.58 (dd, J=7.1, 7.1 Hz, 1H), 5.12 (s, 2H), 4.88(bs, 2H). MS: (calc.) 392.1; (obt.) 393.0 (MH)⁺. 43 211 352

CH CH N-(2-Amino-phenyl)-4-(5-phenyl- [1,2,4]oxadiazol-3-yl)-benzamide¹H NMR: (DMSO) δ (ppm): 9.85 (bs, 1H), 8.24-8.19 (m, 6H), 7.79-7.66 (m,3H), 7.20 (d, J=7.5 Hz, # 1H), 7.00 (dd, J=7.3, 7.3 Hz, 1H), 6.80 (d,J=7.9 Hz, 1H), 6.61 (dd, J=7.3, 7.3 Hz, 1H), 4.96 (bs, 2H). MS: (calc.)356.1; (obt.) 357.0 (MH)⁺. 50 212 353

CH CH N-(2-Amino-phenyl)-4-(5-methyl- [1,2,4]oxadiazol-3-yl)-benzamide¹H NMR: (DMSO) δ (ppm): 9.81 (bs, 1H), 8.17-8.11 (m, 4H), 7.18 (d, J=7.9Hz, # 1H), 6.99 (dd, J=7.7, 7.7 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.61(dd, J=7.5, 7.5 Hz, 1H), 4.94 (bs, 2H), 2.70 (s, 3H). MS: (calc.) 294.1;(obt.) 295.0 (MH)⁺. 50 213 354

CH CHN-(2-Amino-phenyl)-4-(5-piperidin-1-ylmethyl-[1,2,4]oxadiazol-3-yl)-benzamide1H NMR: (acetone) δ (ppm): 9.29 (bs, 1H), 8.21 (m, 4H), 7.31(d, J=8.0Hz,1H), 7.03(dd, J=7.0, 7.0 Hz, 1H), 6.88 (d, J=7.3Hz, 1H), 6.69 (dd,J=7.3, # 7.3 Hz, 1H), 4.68 (bs, 2H), 3.94 (s, 2H), 2.58 (t, J=5.1 Hz),1.63-1.55 (m, 4H), 1.47-1.43 (m, 2H). MS (Calc) 377.2; (Obt.) 378.3(MH)+ 50 214 355

CH CH N-(2-Amino-phenyl)-4-(5- morpholin-4-ylmethyl-[1,2,4]oxadiazol-3-yl)-benzamide 1H NMR: (acetone) δ (ppm): 9.28 (bs,1H), 8.21 (m, 4H), 7.31(d, J=8.1 Hz, 1H), 7.03 (dd, J=7.0, 7.0 # Hz,1H), 6.88 (d, J=7.3 Hz, 1H), 6.69 (dd, J=7.3, 7.3 Hz, 1H), 4.67 (bs,2H), 4.01 (s, 2H), 3.66 (t, J=4.8Hz), 2.65 (t, J=4.4 Hz). MS: (Calc.)379.2; (Obt.): 380.2 (MH)+ 50 215 356

CH CH N-(2-Amino-phenyl)-4-(5-propyl- [1,2,4]oxadiazol-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.62 (s, 1H), 7.93 (d, J=7.9 Hz, 2H),7.42 (d, J=7.9 Hz, 1H), 7.16 (d, J=7.5 Hz, 1H), 6.97 (t, J=7.0 Hz, 1H),6.77 # (d, J=7.9 Hz, 1H), 6.59 (t, J=7.5 Hz, 1H), 4.88 (s, 2H), 4.16 (s,2H), 2.87 (t, 7.0, 2H), 1.72 (q, J=7.5 Hz, 2H), 0.92 (t, J=7.0 Hz, 3H).(MH)⁺: 337.2. 50 216 357

CH CH N-(2-Amino-phenyl)-4-(5-pyridin- 3-yl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.64 (s, 1H), 9.24 d, J=1.8Hz, 1H); 8.86 (dd, J=1.3 Hz, J=4.8 Hz, 1H), 8.45 (dd, J=1.8 Hz, J=6.2Hz, 1H), 7.96 (d, # J=7.9 Hz, 2H), 7.66 (dd, J=4.8 Hz, J=7.9 Hz, 1H),7.50 (d, J=8.4 Hz, 2H), 7.16 (d, J=7.5 Hz, 1H), 6.96 (t, J=7.0 Hz, 1H),6.77 (d, J=7.5 Hz, 1H), 6.59 (t, J=7.5 Hz, 1H), 4.89 (s, 2H), 4.31 (s,2H). (MH)⁺. 372.3. 50 217 358

CH CH N-(2-Amino-phenyl)-4-(5-pyridin- 4-yl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.63 (s, 1H), 8.87 (d, J=6.2Hz, 2H); 7.95-8.02 (m, 3H), 7.50 (d, J=7.9 # Hz, 2H), 7.16 (d, J=7.5 Hz,2H), 6.97 (t, J=7.0 Hz, 1H), 6.77 (d, J=7.0 Hz, 1H), 6.59 (t, J=7.9 Hz,1H), 4.89 (s, 2H), 4.33 (s, 2H). (MH)⁺: 372.3. 50 218 359

CH CH 4-(5-Acetylamino-4-cyano- thiophen-2-ylmethyl)-N-(2-amino-phenyl)-benzamide 1H NMR (DMSO) δ (ppm): 11.62 (s, 1H), 9.60 (bs, 1H),7.93 (d, J=8.1 Hz, 2H), 7.39 (d, J=8.1 Hz, 2H), 6.97 (d, J=7.3 Hz, 1H),7.15 (d, J=7.3 Hz, # 1H), 6.98-6.94 (m, 2H), 6.77 (d, J=7.3 Hz, 1H),6.591 (dd, J=7.7, 7.7 Hz, 1H), 4.89 (bs, 2H), 4.13 (s, 2H), 2.17 (s,3H). LRMS: 390.1 (calc) 391.2 (found). 49 219 360

CH CH 4-(5-Benzoylamino-4-cyano-3- methyl-thiophen-2-ylmethyl)-N-(2-amino-phenyl)-benzamide 1H NMR (DMSO) δ (ppm): 11.77 (s, 1H), 9.61(s, 1H); 7.93 (d, J=7.0 Hz, 4H), 7.52-7.63 (m, 3H), 7.38 (d, J=7.6 Hz,2H), 7.16 (d, J=7.6 Hz, 1H), 6.96 (t, # J=7.6 Hz, 1H), 6.77 (d, J=7.6Hz, 1H), 6.59 (t, J=7.6 Hz, 1H), 4.89 (s, 2H), 4.15 (s, 2H), 2.24 (s,3H). (MH)⁺: 467.0 49 220 361

CH CH N-(2-Amino-phenyl)-4-[4-cyano- 3-methyl-5-(3-phenyl-ureido)-thiophen-2-ylmethyl]-benzamide 1H NMR (DMSO) δ (ppm): 10.12 (s, 1H),9.61 (s, 1H), 9.21 (s, 1H); 7.93 (d, J=7.6 Hz, 2H), 7.27-7.43 (m, 6H),7.16 (d, J=7.6 Hz, 1H), 6.93-7.05 # (m, 2H), 6.77 (d, J=8.2 Hz, 1H),6.59 (t, J=7.6 Hz, 1H), 4.88 (s, 2H), 4.08 (s, 2H), 2.19 (s, 3H). (MH)⁺:482.4 49 221 362

CH CH N-(2-Amino-phenyl)-4-(3-oxo-2,3- dihydro-benzo[1,4]oxazin-4-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.60 (s, 1H), 7.92 (d, J=8.2Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.13 (d, J=6.9 Hz, 1H), 6.92-7.04 (m,5H), 6.75 (dd, # J=8.1 Hz, 1.1 Hz, 1H), 6.57 (td, J=7.4 Hz, 1.4 Hz, 1H),5.24 (s, 2H), 4.88 (bs, 2H); 4.82 (s, 2H). (MH)⁺: 374.1 11 222 363

CH CH N-(2-Amino-phenyl)-4-(3-oxo- 2,3-dihydro-benzo[1,4]thiazin-4-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.58 (s, 1H), 7.90 (d,J=8.2 Hz, 2H), 7.42 (dd, J=8.0 Hz, J=1.4 Hz, 1H), 7.32 (d, J=8.2 Hz,2H), 7.19-7.11 (m, 3H), 7.04-6.92 # (m, 2H), 6.75 (dd, J=8.0 Hz, 1.4 Hz,1H), 6.57 (td, J=8.0 Hz, 1.6 Hz, 1H), 5.31 (s, 2H); 4.88 (bs, 2H); 3.70(s, 2H). (MH)⁺: 390.1 11 223 364

CH CH N-(2-Amino-phenyl)-4-(3-oxo-2,3- dihydro-pyrido[3,2-b][1,4]oxazin-4-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.57 (bs, 1H), 7.98 (d,J=4.7 Hz, 1H), 7.89 (d, J=8.2 Hz, 2H), 7.45-7.40 (m, 3H), 7.15 (d, J=8.2Hz, 1H), 7.09-7.05 # (m, 1H), 6.96 (dd, J=7.6, 7.6 Hz, 1H), 6.76 (d,J=8.2 Hz, 1H), 6.58 (dd, J=7.6, 7.6 Hz, 1H), 5.31 (s, 2H), 4.90 (bs,2H), 4.87 (s, 2H). (MH)⁺: 375.1 11 224 365

CH CH N-(2-Amino-phenyl)-4-(1-hydroxy- 3-oxo-indan-2-ylmethyl)-benzamide ¹H NMR: (DMSO) δ (ppm): 9.67 (s, 1H); 7.98 (d, J=8.2 Hz, 2H),7.73-7.84 (m, 3H), 7.53-7.62 (m, 3H), 7.24 (d, J=7.6 Hz, 1H), 7.04 (t,J=7.6 Hz, 1H), 6.85 (d, J=8.2 Hz, # 1H), 6.67 (t, J=7.6 Hz, 1H), 5.68(d, J=7.0 Hz, 1H), 5.27 (t, J=6.4 Hz, 1H), 4.95 (s, 2H), 3.21-3.30 (m,1H), 3.11-3.13 (m, 2H). (MH)⁺: 373.1 46 225 366

CH CH N-(2-Amino-phenyl)-4- phenoxy-benzamide ¹H NMR: (DMSO) δ (ppm):9.61 (s, 1H); 8.01 (d, J=8.8 Hz, 2H), 7.45 (t, J=7.6 Hz, 2H), 7.06-7.24(m, 6H), 6.97 (t, J=1.6 Hz, 1H), 6.78 (d, J=7.4 Hz, 1H), 6.59 (t, J=7.6Hz, 1H), 4.88 (s, 2H). (MH)⁺: 305.0  1 226 367

CH CH N-(2-Amino-phenyl)-4-[5-(4- methoxy-phenyl)-2,5-dihydro-furan-2-yl]-benzamide ¹H NMR (CDCl₃) δ (ppm): 8.77 (s,1H), 7.93 (d,J=8.1 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.38-6.98 (m, 6H), 6.91 (d,J=8.4Hz, 2H), 6.09-5.98 (m, 4H), 3.81 (s, 3H). 52 230 371

CH CH N-(2-Amino-phenyl)-4-[1,3-bis- (3,4-dimethoxy-phenyl)-ureidomethyl]-benzamide ¹H NMR (DMSO-d₆): δ 10.08 (brs, 1H), 7.99 (d,J=7.9 Hz, 2H), 7.70 (s, 1H), 7.49 (d, J=8.35 Hz, 4H), 7.39-7.33 (m, 1H),7.30-6.90 (m, 7H), 6.87 (dd, # J=2.2, 8.35 Hz, 1H), 6.78 (dd, J=2.2,8.35 Hz, 1H), 5.01 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H), 3.75 (s, 6H). 57231 372

CH CH N-(2-Amino-phenyl)-4-[3-(4- chloro-phenyl)-1-(3,4-dimethoxy-phenyl)-ureidomethyl]-benzamide ¹H NMR (CDCl₃): δ 8.02 (brs, 1H), 7.90(d, J=7.9 Hz, 2H), 7.46 (d, J=7.5 Hz, 2H), 7.42-7.24 (m, 6H), 7.16 (t,J=7.5 Hz, 1H), 6.91 (brd, J=5.71 Hz, 3H), 6.75 # (brd, J=8.3 Hz, 1H),6.70 (d, J=1.8 Hz, 1H), 4.99 (s, 1H), 3.97 (s, 3H), 3.86 (s, 3H). 57 232373

CH CH N-(2-Amino-phenyl)-4-[1-(3,4- dimethoxy-phenyl)-3-phenyl-ureidomethyl]-benzamide ¹H NMR (DMSO-d₆): δ 10.10 (brs, 1H), 7.99 (d,J=7.9 Hz, 2H), 7.88 (s, 1H), 7.80-7.72 (m, 1H), 7.50 (dd, J=7.0, 5.7 Hz,4H), 7.37 (d, J=7.9 # Hz, 1H), 7.30-6.94 (m, 7H), 6.78 (d, J=6.6 Hz,1H), 5.03 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). 57 233 374

CH CH N-(2-Amino-phenyl)-4-[1-(3,4- dimethoxy-phenyl)-3-(4-phenoxy-phenyl)-ureidomethyl]-benzamide ¹H NMR (CDCl₃): δ 8.02 (brs, 1H), 7.92(d, J=7.9 Hz, 2H), 7.49 (d, J=8.35 Hz, 2H), 7.43-7.32 (m, 5H), 7.10-7.30(2m, 5H), 7.19-7.10 (m, 2H), # 7.01 (dd, J=8.35, 2.2 Hz, 3H), 6.94 (d,J=7.5 Hz, 1H), 6.92 (d, J=8.8 Hz, 1H), 6.77 (dd, J=8.8, 2.2 Hz, 1H),6.72 (d, J=2.2 Hz, 1H), 6.34 (s, 2H), 5.02 (s, 2H), 3.98 (s, 3H), 3.87(s, 3H). 57 234 375

CH CH Biphenyl-4,4′-dicarboxylic acid bis-[(2-amino-phenyl)-amide] ¹HNMR (CD₃OD) δ (ppm): 9.80 (bs, 2H), 8.16 (d, J=7.9 Hz, 4H), 7.96 (d,J=7.9 Hz, 4H), 7.23 (d, J=7.4 Hz, 2H), 7.03 (dd, J=6.9, 7.4 Hz, 2H),6.84 (d, J=8.2 Hz, 2H), 6.66 (dd, J=6.9, 7.7 Hz, 2H), 5.06 (bs, 4H). 15236 377

CH CH N-(2-Amino-phenyl)-4-(pyrimidin- 2-ylaminomethyl)-benzamide ¹H-NMR(DMSO-d6), δ (ppm): 9.6 (bs, 1H), 8.32 (d, J=4.9 Hz, 2H), 7.97 (dt,J=7.9, 9.9 Hz, 2H), 7.85-7.83 (m, 1H), 7.47, (d, J=8.2 Hz, 2H), 7.20 (d,# J=7.9 Hz, 1H), 7.01 (dt, J=7.4, 7.7 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H),6.66-6.62 (m, 1H), 4.98 (bs, 2H), 4.61 (d, 2H). 13 237 378

CH CH N-(2-Amino-phenyl)-4-(4,6- dimethyl-pyrimidin-2-ylsulfanyl-methyl)-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.96 (d,J=7.9 Hz, 2H), 7.61 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.9 Hz, 1H), 7.04-6.99(m, 2H), 6.82 (d, # J=7.9 Hz, 1H), 6.64 (t, J=7.4 Hz, 1H), 4.49 (s, 2H),2.42 (s, 6H). 11 238 379

CH CH N-(2-Amino-phenyl)-4-(4- trifluoromethyl-pyrimidin-2-ylsulfanylmethyl)-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H),9.07 (d, J=5.2 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 7.78 (d, J=4.7 Hz, 1H),7.63 (d, J=7.4 Hz, 2H), 7.19 (d, J=7.7 Hz, # 1H), 7.01 (dt, J=7.4, 7.7Hz, 1H), 6.81 (d, J=8.2 Hz, 1H), 6.64 (dt, J=7.1, 7.4 Hz, 1H), 4.94 (bs,2H), 4.57 (s, 2H). 11 239 380

N CH Pyridine-2,5-dicarboxylic acid bis-[(2-amino-phenyl)-amide] ¹H-NMR(DMSO-d6), δ (ppm): 10.23 (bs, 1H), 10.04 (bs, 1H), 9.30 (s, 1H), 8.62(dd, J=1.8, 8.0 Hz, 1H), 8.30 (d, J=8.1 Hz, 1H), 7.55 (d, J=7.4 Hz, 1H),# 7.24 (d, J=7.4 Hz, 1H), 7.04 (dd, J=7.0, 14.0 Hz, 2H), 6.90-6.83 (m,2H), 6.74-6.63 (m, 2H), 5.11 (bs, 4H). 240 381

CH CH N-(2-Amino-phenyl)-4-(pyridin- 2-ylsulfanylmethyl)-benzamide¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 8.52 (bs, 1H), 7.96 (d, J=7.4Hz, 2H), 7.69 (d, J=5.8 Hz, 1H), 7.59 (d, J=7.4 Hz, 2H), 7.38 (d, J=7.7Hz, 1H), 7.19 (bs, 2H), 7.00 # (d, J=6.9 Hz, 1H), 6.83 (d, J=6.9 Hz,1H), 6.64 (dd, J=6.7, 7.2 Hz, 1H), 4.94 (bs, 2H), 4.55 (b + s, 2H). 11241 382

CH CH N-(2-Amino-phenyl)-4-[(4,6- dimethyl-pyrimidin-2-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.65 (bs, 1H), 7.96 (d,J=7.9 Hz, 2H),7.57 (d, J=6.3 Hz, 1H), 7.47 (d, J=7.7 Hz, 2H), 7.21 (d,J=7.4 Hz, 1H), 7.00 (d, # J=5.8 Hz, 1H), 6.59 (d, J=6.6 Hz, 1H), 6.64(dd, J=6.0, 7.4 Hz, 1H), 5.01 (s, 2H), 4.61 (d, J=6.0 Hz, 2H), 2.24 (s,6H). 33 242 383

CH CH N-(2-Amino-phenyl)-4-[(4,6- dimethyl-pyridin-2-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.98 (d,J=7.9 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.96 (d, J=7.9 Hz, 1H), 7.01 (dd,J=7.7, 7.4 Hz, 1H), 6.82 # (d, J=7.9 Hz, 1H), 6.64 (t, J=7.4 Hz, 1H),6.33 (s, 1H), 6.25 (s, 1H), 4.58 (d, J=4.4 Hz, 2H), 2.28 (s, 3H), 2.17(s, 3H). 243 384

CH CH N-(2-Amino-phenyl)-4-(4,6- dimethyl-pyrimidin-2-yloxymethyl)-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.58 (bs, 1H), 7.88(d, J=5.8 Hz, 2H),7.46 (d, J=8.2 Hz, 2H), 6.90-6.81 (m, 1H), 6.68 (d,J=7.9 Hz, 1H), 6.50 (t, J=7.4 # Hz, 1H), 6.40-6.38 (m, 1H), 6.29-6.26(m, 1H), 5.33 (s, 2H), 2.25 (s, 6H). 11 244 385

CH CH N-(2-Amino-phenyl)-4-[(6- methoxy-pyrimidin-4-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.64 (bs, 1H), 8.21 (bs, #1H), 7.95 (d, J=7.96 Hz, 2H), 7.83 (d, J=5.8 Hz, 1H), 7.44 (d, J=7.9Hz,2H), 7.19 (d, J=7.7 Hz, 1H), 7.00 (dd, J=7.4, 7.7 Hz, 1H), 6.80 (d,J=7.9 Hz, 1H), 6.64 (d, J=7.1 Hz, 1H), 4.96 (bs, 2H), 4.58 (bs, 2H),3.81 (s, 3H). 33 245 386

CH CH 4-[(6-Acetyl-benzo[1,3]dioxol- 5-ylamino)-methyl]-N-(2-amino-phenyl)-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.79 (bs, 1H), 7.99 (d,J=8.5 Hz, 2H), 7.48 (d, J=7.96 Hz, 2H), 7.39 (bs, 1H), 7.21 (d, J=7.4Hz, 1H), 7.02 # (dd, J=7.1, 7.7 Hz, 1H), 6.83 (d, J=7.7 Hz, 1H), 6.64(t, J=7.4 Hz, 1H), 6.36 (bs, 1H), 6.00 (d, J=2.2 Hz, 2H), 4.59 (bs, 2H),2.52 (bs, 3H). 33 246 387

CH CH N-(2-Amino-phenyl)-4-[(4-chloro- 6-methoxy-pyrimidin-2-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.96 (d,J=7.9 Hz, 2H), 7.47 (bs, 2H), 7.39 (bs, 1H), 7.19 (d, J=7.4 Hz, 1H),7.00 (dd, # J=6.9, 7.4 Hz, 1H), 6.81 (d, J=7.1 Hz, 1H), 6.63 (dd, J=7.7,6.8 Hz, 1H), 6.10 (bs, 1H), 4.56 (d, J=6.0 Hz,, 2H), 3.83 (s, 3H). 33247 388

CH CH N-(2-Amino-phenyl)-4-[(2,6- dimethoxy-pyridin-3-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.63 (bs, 1H), 7.94 (d,J=6.9 Hz, 2H), 7.47 (d, J=6.59 Hz, 2H), 7.15 (d, J=7.9 Hz, 1H), 6.99(dd, J=5.7, 7.4 Hz, 1H), 6.80 (d, # J=7.8 Hz, 1H), 6.71 (d, J=6.6 Hz,1H), 6.62 (dd, J=7.7, 7.1 Hz, 1H), 6.15 (d, J=8.2 Hz, 1H), 4.96 (bs,2H), 4.38 (bs, 2H), 3.94 (s, 3H), 3.75 (s, 3H). 33 248 389

CH CH N-(2-Amino-phenyl)-4-[(1H- benzoimidazol-2-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 10.9 (bs, 1H), 9.64 (bs,1H), 7.99 (bs, 2H), 7.55 (bs, 2H), 7.21-7.17 (m, # 3H), 7.14-6.81 (m,4H), 6.64 (d, J=6.0 Hz, 1H), 4.92 (bs, 2H), 4.65 (bs, 2H). 33 249 390

CH CH N-(2-Amino-phenyl)-4-[(6- methoxy-pyridin-2-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.60 (bs, 1H), 7.96 (d,J=7.9 Hz, 1H), 7.52-7.50 (m, 2H), 7.37-7.30 (m, 1H), 7.25-7.21 (m, 2H),7.19-6.99 (m, 1H), 6.84-6.81 # (m, 1H), 6.67-6.64 (m, 1H), 6.11-6.07 (m,1H), 5.93-5.89 (m, 1H), 4.93 (bs, 2H), 4.56 (d, J=5.8 Hz, 2H), 3.80 (s,3H). 37 250 391

CH CH N-(2-Amino-phenyl)-4-(quinolin- 8-ylsulfanylmethyl)-benzamide¹H-NMR (DMSO-d6), δ (ppm): 9.68 (bs, 1H), 8.95 (bs, 2H), 8.43-8.38 (m,1H), 7.90 (bs, 2H), 7.80-7.55 (m, 6H), 7.22 (d, J=7.7 Hz, 1H), 7.03 (d,# J=7.7 Hz, 1H), 6.63 (d, J=7.4 Hz, 1H), 5.05 (bs, 2H), 4.48 (d, J=7.7,2H). 11 251 392

CH CH N-(2-Amino-phenyl)-4-[(2,6- dimethoxy-pyrimidin-4-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.97 (d,J=7.9 Hz, 2H), 7.84 (t, J=5.9 Hz, 1H), 7.46 (d, J=7.46 Hz, 2H), 7.20 (d,J=7.9 Hz, 1H), 7.04 # (d, J=6.6 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.64(dd, J=7.7, 7.4 Hz, 1H), 5.51 (bs, 1H), 4.57 (bs,, 2H), 3.82 (s, 3H),3.84 (s, 3H). 37 252 393

CH CH N-(2-Amino-phenyl)-4-(3,5- dimethoxy-benzylamino)- benzamide¹H-NMR (DMSO-d6), δ (ppm): 9.63 (bs, 1H), 7.79 (d, J=8.5 Hz, 2H), 7.19(d, J=6.6 Hz, 1H), 7.00 (dd, J=7.9, 7.1 Hz, 1H), 6.62 (t, J=6.0 Hz, 1H),6.82 (dd, J=1.4, 7.9 Hz, # 1H), 6.67 (d, J=8.8 Hz, 2H), 6.58 (bs, 2H),6.42 (bs, 1H), 4.87 (bs, 2H), 4.34 (d, J=6.0 Hz, 2H), 3.77 (s, 6H). 37253 394

CH CH N-(2-Amino-phenyl)-4-(3- methoxy-phenylsulfanylmethyl)- benzamide¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 7.96 (d, J=7.9 Hz, 2H), 7.55(d, J=8.2 Hz, 2H), 7.29-7.20 (m, 2H), 7.02-6.95 (m, 2H), 6.84-6.79 (m,1H), # 6.67-6.62 (m, 1H), 6.57-6.54 (m, 1H), 6.44-6.41 (m, 1H), 4.93(bs, 2H), 4.41 (bs, 2H), 3.79 (s, 3H). 11 254 395

CH CH N-(2-Amino-phenyl)-4-(3,5- dimethoxy-phenoxymethyl)- benzamide¹H-NMR (DMSO-d6), δ (ppm): 9.72 (bs, 1H), 8.05 (d, J=8.2 Hz, 2H), 7.61(d, J=7.9 Hz, 2H), 7.24 (d, J=7.4 Hz, 1H), 7.04 (dd, J=6.9, 7.1 Hz, 1H),6.85 (d, # J=6.9 Hz, 1H), 6.66 (dd, J=7.4, 7.7 Hz, 1H), 6.27 (s, 2H),6.26 (s, 1H), 5.23 (s, 2H), 5.21 (bs, 2H), 3.77 (s, 6H). 11 255 396

CH CH N-(2-Amino-phenyl)-4-(quinolin- 2-yloxymethyl)-benzamide ¹H-NMR(DMSO-d6), δ (ppm): 9.70 (bs, 1H), 8.35 (d, J=9.1 Hz, 2H), 8.05 (d,J=7.9 Hz, 2H), 7.96 (d, J=7.9 Hz, 1H), 7.85 (d, J=8.2 Hz, 1H), 7.76-7.69(m, # 2H), 7.51 (dd, J=6.9, 7.1 Hz, 1H), 7.24-7.16 (m, 2H), 7.02 (dd,J=6.9, 7.4 Hz, 1H), 6.83 (d, J=8.2 Hz, 1H), 6.66 (d, J=7.4 Hz, 1H), 5.66(s, 2H), 4.94 (bs, 2H). 11 256 397

CH CH N-(2-Amino-phenyl)-4-[(3,5- dimethoxy-phenylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.62 (bs, 1H), 7.96 (d,J=7.9 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.19 (d, J=7.9 Hz, 1H), 7.00 (dd,J=7.5, 7.9 Hz, # 1H), 6.81 (d, J=7.9 Hz, 1H), 6.63 (dd, J=7.0, 8.0 Hz,1H), 5.78 (s, 2H), 5.76 (s, 1H), 4.92 (bs,, 2H), 4.35 (d, J=5.7, 2H),3.65 (s, 6H). 33 257 398

CH N bis(N-(2-Amino-phenyl)- nicotinamide)-6-disulfide ¹H-NMR (DMSO-d6),δ (ppm): 9.82 (bs, 2H), 9.08 (bs, 2H), 8.34 (d, J=8.3 Hz, 2H), 7.83 (d,J=8.3 Hz, 2H), 7.18 (d, J=7.5 Hz, 2H), 7.01 (dd, J=6.3, 7.0 Hz, # 2H),6.80 (d, J=7.9 Hz, 2H), 6.61 (t, J=7.03 Hz, 2H), 5.05 (bs, 4H).  1 258399

CH CH N-(2-Amino-phenyl)-4- (isoquinolin-1-ylaminomethyl)- benzamide¹H-NMR (DMSO-d6), δ (ppm): 9.90 (bs, 1H), 8.16 (bs, 2H), 7.65 (d, J=4.8Hz, 2H), 7.54 (bs, 2H), 7.25 (d, J=7.0 Hz, 2H), 7.11 (bs, 2H), #7.07-7.02 (m, 2H), 6.84 (d, J=7.9 Hz, 1H), 6.67 (bs, 1H), 5.01 (bs, 2H),4.88 (bs, 2H). 33 259 400

CH CH N-(2-Amino-phenyl)-4-[(2,3- dihydro-benzo[1,4]dioxin-6-ylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H),7.97 (d, J=7.0 Hz, 2H), 7.51 (d, J=7.0 Hz, 2H), 7.22 (d, # J=7.5 Hz,1H), 7.02-6.97 (m, 1H), 6.84 (bs, 1H), 6.82-6.71 (m, 2H), 6.16 (d, J=6.6Hz, 1H), 6.08 (s, 1H), 4.32 (bs, 2H), 4.16-4.13 (m, 4H). 33 260 401

CH CH 4-[(4-Acetylamino-phenylamino)- methyl]-N-(2-amino-phenyl)-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.66 (bs, 1H), 9.56 (bs, 1H), 7.97(d, J=7.9 Hz, 2H), 7.53 (d, J=7.9 Hz, 2H), 7.28 (d, J=8.8 Hz, 2H), 7.22(d, J=7.9 # Hz, 1H), 7.02 (t, J=7.5 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H),6.65 (t, J=7.5 Hz, 1H), 6.55 (d, J=8.3 Hz, 2H), 4.98 (bs, 2H), 4.38 (bs,2H), 2.00 (s, 3H). 33 261 402

CH CH N-(2-Amino-phenyl)-4-[(4- morpholin-4-yl-phenylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.65 (bs, 1H), 7.98 (d,J=7.9 Hz, 2H), 7.52 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H), 7.02 (dd,J=7.0, 7.9 Hz, 1H), 6.83 (d, # J=7.9 Hz, 1H), 6.78 (d, J=8.8 Hz, 2H),6.64 (t, J=7.5 Hz, 1H), 6.55 (d, J=8.8 Hz, 2H), 4.94 (bs, 2H), 4.35 (d,J=5.7 Hz, 2H), 3.74 (t, J=4.4 Hz, 4H), 2.92 (t, J=4.4 Hz, 4H). 33 262403

CH CH N-(2-Amino-phenyl)-4-[(4- methoxy-2-methyl-phenylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.64 (bs, 1H), 7.96 (d,J=7.6 Hz, 2H), 7.52 (d, J=7.6 Hz, 2H), 7.21 (d, J=8.2 Hz, 1H), 7.02 (t,J=8.2, 7.0 Hz, 1H), 6.83 (d, # J=8.2 Hz, 1H), 6.71-6.53 (m, 3H),6.32-6.30 (m, 1H), 4.94 (bs, 2H), 4.45 (d, J=5.9 Hz, 2H), 3.65 (s, 3H),2.23 (s, 3H). 33 263 404

CH CH N-(2-Amino-phenyl)-4-[(2-cyano- 4-methoxy-phenylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.65 (bs, 1H), 7.98 (d, J=7.4 Hz,2H), 7.56 (d, J=7.5 Hz, 2H), 7.19 (d, J=7.9 Hz, 1H), 6.99 (d, J=7.5 Hz,1H), 6.82 (d, # J=7.9 Hz, 1H), 6.63 (t, J=6.6 Hz, 2H), 6.27 (s, 1H),4.93 (bs, 2H), 4.55 (d, J=5.3 Hz, 2H), 3.69 (s, 6H). 33 264 405

CH CH N-(2-Amino-phenyl)-4-{[4- methoxy-3-(pyridin-3-ylmethoxy)-phenylamino]-methyl}-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.62 (s, 1H),8.72 (s, 1H), 8.49 (d, J=10.1 Hz, 1H), 7.93 (d, J=7.9 Hz, 2H), 7.68 #(d, J=6.6 Hz, 1H), 7.37 (d, J=7.5 Hz, 2H), 7.16 (d, J=7.5 Hz, 1H), 6.97(t, J=7.5 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H), 6.69 (d, J=8.8 Hz, 1H), 6.62(d, J=7.5 Hz, 1H), 6.23 (d, J=2.6 Hz, 1H), 6.09 (J=8.8 Hz, 1H), 5.76 (s,1H), 4.64 (bs, 4H), 3.62 (s, 3H). 33 265 406

CH CH 2-[4-(2-Amino-phenylcarbamoyl)- benzylamino]-4,5-dimethoxy-benzoic acid ¹H-NMR (DMSO-d6), δ (ppm): 9.67 (bs, 1H), 8.00 (d, J=7.9Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.34 # (s, 1H), 7.20 (d, J=7.9 Hz, 2H),7.0 (t, J=7.9 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 6.62 (t, J=7.9 Hz, 1H),6.31 (s, 1H), 4.95 (bs, 2H), 4.62 (bs, 2H), 3.75 (s, 3H), 3.70 (s, 3H).33 266 407

CH CH N-(2-Amino-phenyl)-4-[(3,5- dimethyl-phenylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.60 (s, 1H), 7.93 (d, J=7.9 Hz,2H), 7.45 (d, J=7.9 Hz, 2H), 7.16 (d, J=7.5 Hz, 1H), 6.97 (t, J=7.5 Hz,1H), 6.78 (d, J=7.9 # Hz, 1H), 6.58 (t, J=7.0 Hz, 1H), 6.19-6.17 (m,3H), 4.88 (s, 2H), 4.32 (d, J=5.7 Hz, 2H), 2.10 (s, 6H). 33 267 408

CH CH N-(2-Amino-phenyl)-4-{[4- (pyridin-3-ylmethoxy)-phenylamino]-methyl}-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.65 (s, 1H),8.72 (s, 1H), 8.54 (s, 1H), 8.49 (d, J=10.9 Hz, 1H), # 7.97 (d, J=7.9Hz, 2H), 7.71 (d, J=7.9 Hz, 1H), 7.44 (d, J=8.3 Hz, 2H), 7.41-7.36 (m,1H), 7.20 (d, J=7.9 Hz, 1H), 7.00 (t, J=7.4 Hz, 1H), 6.83 (d, J=7.0 Hz,1H), 6.70-6.60 (m, 4H), 4.62 (s, 4H). 33 268 409

CH CH N-(2-Amino-phenyl)-4-[(2,4- dimethyl-phenylamino)-methyl]-benzamide ¹H-NMR (DMSO-d6), δ (ppm): 9.58 (s, 1H), 7.90 (d, J=7.9 Hz,2H), 7.45 (d, J=7.5 Hz, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.96 (t, J=7.5 Hz,1H), 6.79 (s, 1H), 6.76 # (d, J=9.6 Hz, 1H), 6.68 (d, J=7.9 Hz, 1H),6.59 (t, J=7.0 Hz, 1H), 6.22 (d, J=7.9 Hz, 1H), 4.89 (bs, 2H), 4.39 (d,J=5.7 Hz, 2H), 2.15 (s, 3H), 2.10 (s, 3H). 33 269 410

CH CH N-(2-Amino-phenyl)-4-[(2,4,6- trimethyl-phenylamino)-methyl]-benzamide ¹H-NMR (CD₃OD), δ (ppm): 7.91 (d, J=7.9 Hz, 2H), 7.43 (d,J=8.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.92 (d,J=7.9 # Hz, 1H), 6.77 (s, 3H), 4.15 (bs, 2H), 2.19 (s, 9H). 33 270 411

CH CH N-(2-Amino-phenyl)-4-[(4-chloro- 6-morpholin-4-yl-pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-D6) δ *** (ππμ): 9.66(s, 1H), 7.97 (d, J=8.0 Hz, 2H), 7.82 (m, 1H), 7.47 (d, # J=7.7 Hz, 2H),7.21 (d, J=8.2 Hz, 1H), 7.03 (dd, J=7.1, 7.1 Hz, 1H), 6.84 (d, J=7.7 Hz,1H), 6.65 (dd, J=7.4, 7.4 Hz, 1H), 6.17 (bs, 1H), 4.94 (s, 2H, NH₂),4.53 (d, J=5.8 Hz, 2H), 3.58 (m, 4H), 3.62 (m, 4H). 24, 33 271 412

CH CH N-(2-Amino-phenyl)-4-(3,4,5- trimethoxy-benzylamino)- benzamide ¹HNMR (300 MHz, DMSO-d₆) δ (ppm): 9.33 (s, 1H), 7.81 (d, J=8.8 Hz, 2H),7.19 (d, J=7.7 Hz, 1H), # 6.99 (m, 1H), 6.87 (dd, J=6.0, 5.8 Hz, 1H),6.82 (m, 1H), 6.77 (s, 2H), 6.71 (d, J=8.8 Hz, 2H), 6.64 (m, 1H), 4.87(s, 2H, NH₂), 4.32 (d, J=5.5 Hz, 2H), 3.81 (s, 6H), 3.79 (s, 3H). 33 272413

CH CH N-(2-Amino-phenyl)-4-(4-fluoro- benzylamino)-benzamide ¹H NMR (300MHz, DMSO-d₆) δ δ (ppm): 9.31 (s, 1H), 7.79 (d, J=8.7 Hz, 2H), 7.45 (dd,J=5.8, 8.5 Hz, # 2H), 7.21 (m, 3H), 6.91 (m, 2H), 6.81 (dd, J=1.1,8.0Hz, 1H), 6.67 (d, J=8.8 Hz, 2H), 6.62 (dd, J=1.0, 7.2 Hz, 1H), 4.86(s, 2H, NH₂), 4.39 (d, J=6.0 Hz, 2H). 33 273 414

CH CH N-(2-Amino-phenyl)-4-(4- methoxy-benzylamino)-benzamide ¹H NMR(300 MHz, DMSO-d₆) δ (ppm): 9.31 (s, 1H), 7.79 (dd, J=1.1, 8.5 Hz, 2H),7.33 (d, J=7.1 # Hz, 2H), 7.19 (d, J=7.7 Hz, 1H), 6.97 (m, 3H), 6.84 (m,2H), 6.65 (m, 3H), 4.86 (s, 2H, NH₂), 4.33 (d, J=5.5 Hz, 2H), 3.58 (d,J=1.6 Hz, 3H). 33 274 415

CH CH N-(2-Amino-phenyl)-4-[(4-fluoro- phenylamino)-methyl]-benzamide ¹HNMR (300 MHz, DMSO-d₆) δ (ppm): 9.66 (s, 1H), 7.99 (d, J=7.9 Hz, 2H),7.53 (d, J=8.0 Hz, 2H), # 7.21 (d, J=8.0 Hz, 1H), 7.02 (ddd J=1.6, 7.1,8.2 Hz, 1H), 6.93 (dd, J=8.8, 9 Hz, 2H), 6.83 (dd, J=1.1, 8.0 Hz, 1H),6.63 (m, 3H), 6.35 (t, J=6.2 Hz, 1H), 4.94 (s, 2H, NH₂), 4.38 (d, J=6.3Hz, 2H). 33 275 416

CH CH N-(2-Amino-phenyl)-4-(3-fluoro- benzylamino)-benzamide ¹H NMR (300MHz, DMSO-d₆) δ (ppm): 9.32 (s, 1H), 7.79 (d, J=8.8 Hz, 2H), 7.44 (m,1H), 7.26 (m, 1H), 7.18 (dd, J=1.4, # 8.0 Hz, 2H), 7.12 (ddd, J=1.7,8.0, 8.2 Hz, 1H), 6.99 (m, 2H), 6.81 (dd, J=1.4, 8.0 Hz, 1H), 6.67 (dd,J=1.6, 8.8 Hz, 2H), 6.62 (dd, J=1.4, 7.4 Hz, 1H), 4.87 (s, 2H, NH₂),4.45 (d, J=6.0 Hz, 2H). 33 276 417

CH CH N-(2-Amino-phenyl)-4-[(3-fluoro- phenylamino)-methyl]-benzamide ¹HNMR (300 MHz, DMSO-d₆) δ (ppm): 9.66 (s, 1H), 7.99 (d, J=8.2 Hz, 2H),7.52 (d, J=8.0 Hz, 2H), 7.21 (d, J=7.7 Hz, 1H), 6.99-7.14 (m, 2H), 6.83# (d, J=8.0 Hz, 1H), 6.76 (m, 1H), 6.64 (dd, J=7.4, 7.4 Hz, 1H), 6.46(d, J=8.2 Hz, 1H), 6.34 (m, 2H), 4.94 (s, 2H, NH₂), 4.41 (d, J=6.0 Hz,2H). 33 277 418

CH CH N-(2-Amino-phenyl)-4-[(4-chloro- 6-methyl-pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-D₆) δ (ppm): 9.66 (s, 1H), 8.23(m, 1H), 7.98 (d, J=8.2 Hz, 2H), 7.47 (d, # J=8.5 Hz, 2H), 7.21 (d,J=7.7 Hz, 1H), 7.03 (ddd, J=1.5, 7.1, 8.0 Hz, 1H), 6.83 (dd, J=1.5, 8.1Hz, 1H), 6.65 (m, 2H), 4.94 (s, 2H, NH₂), 4.61 (m, 2H), 2.3 2 (s, 3H).33 278 419

CH CH N-(2-Amino-phenyl)-4-[(4,6- dichloro-pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-D₆) δ (ppm): 9.69 (s, 1H), 8.82(m, 1H), 7.99 (d, J=8.2 Hz, 2H), 7.48 (d, J=8.0 # Hz, 2H), 7.27 (d,J=7.7 Hz, 1H), 7.04 (d, J=7.7 Hz, 1H), 7.0 (d, J=1.6 Hz, 1H), 6.84 (d,J=8.2Hz, 1H), 6.67 (m, 1H), 5.0 (bs, 2H, NH₂), 4.60 (d, J=6.3 Hz, 2H).33 279 420

CH CH N-(2-Amino-phenyl)-4-({4-chloro- 6-[(pyridin-3-ylmethyl)-amino]-pyrimidin-2-ylamino}-methyl)- benzamide ¹H NMR (300 MHz, DMSO-D₆) δ(ppm): 9.87 (s, 1H), 8.49 (bs, 2H), 7.26-8.02 (bm, 8H), 7.22 (d, # J=8.0Hz, 1H), 7.03 (dd, J=7.4, 7.4 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.66 (dd,J=7.1, 8.0 Hz, 1H), 5.86 (bs, 1H), 4.95 (s, 2H, NH₂), 4.51 (m, 2H). 24,33 280 421

CH CH N-(2-Amino-phenyl)-4-[(6- methoxy-pyridin-3-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-D₆) δ (ppm): 9.66 (s, 1H), 7.99(d, J=8.4 Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.50 (d, J=2.6 Hz, 1H), 7.21(d, # J=7.5 Hz, 7.9 Hz, 1H), 7.12 (dd, J=3.08 Hz, 8.79 Hz, 1H), 7.02(dd, J=7.0 Hz, 7.5 Hz, 1H), 6.83 (d, J=7.0 Hz, 1H), 6.65 (m, 2H), 6.15(t, J=6.16 Hz, 1H), 4.94 (s, 2H, NH₂), 4.39 (d, J=6.15 Hz, 2H), 3.75 (s,3H). 33 281 422

CH CH N-(2-Amino-phenyl)-4-[(4- trifluoromethoxy-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.66 (s, 1H), 7.99(d, J=8.0 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), # 7.21 (d, J=7.7 Hz, 1H),7.09 (d, J=9.1 Hz, 2H), 7.03 (dd, J=7.1, 8.2 Hz, 1H), 6.83 (d, J=8.0 Hz,1H), 6.71 (t, J=6.0 Hz, 1H), 6.63-6.67 (m, 3H), 4.94 (s, 2H, NH₂), 4.42(d, J=6.0 Hz, 2H). 33 282 423

CH CH N-(2-Amino-phenyl)-4-[(3- trifluoromethoxy-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.67 (s, 1H), 8.00(d, J=8.2 Hz, 2H), 7.53 (d, J=8.2 Hz, 2H), 7.19 (m, 2H), 7.03 (ddd, #J=1.5, 8.0, 8.8 Hz, 1H), 6.85 (m, 2H), 6.63 (m, 2H), 6.55 (s, 1H), 6.50(m, 1H), 4.94 (s, 2H, NH₂), 4.44 (d, J=6.0 Hz, 2H). 33  283a  424b

CH CH N-(2-Amino-phenyl)-4-[(3,4- dimethoxy-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.65 (s, 1H), 7.98 (d,J=7.9 Hz, 2H), 7.54 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.02 #(dd, J=7.9 Hz, 7.9 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.79 Hz,1H), 6.45 (dd, J=7.49 Hz, 7.49 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H),6.01-6.08 (m, 2H), 4.94 (s, 2H, NH₂), 4.36 (d, J=6.16 Hz, 2H), 3.72 (s,3H), 3.65 (s, 3H). 33 284 425

CH CH N-(2-Amino-phenyl)-4-(3- trifluoromethoxy-benzylamino)- benzamide¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.31 (s, 1H), 7.80 (d, J=8.8 Hz, 2H),7.45-7.56 (m, 2H), 7.39 (s, 1H), 7.29 (d, J=7.7 Hz, 1H), 7.18 (d, J=6.6# Hz, 1H), 6.96-7.03 (m, 2H), 6.81 (d, J=6.9 Hz, 1H), 6.68 (d, J=8.8 Hz,2H), 6.64 (d, J=7.7 Hz, 1H), 4.86 (s, 2H, NH₂), 4.48 (d, J=5.8 Hz, 2H).33 285 426

CH CH N-(2-Amino-phenyl)-4-(4- trifluoromethoxy-benzylamino)- benzamide¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.31 (s, 1H), 7.79 (d, J=8.8 Hz, 2H),7.54 (d, J=8.8 Hz, 2H), # 7.39 (d, J=8.0 Hz, 2H), 7.18 (dd, J=1.4, 7.7Hz, 1H), 6.99 (ddd, J=1.4, 8.0, 8.5 Hz, 2H), 6.81 (dd, J=1.4, 8.0, 1H),6.68 (d, J=8.8 Hz, 2H), 4.85 (s, 2H, NH₂), 4.45 (d, J=6.0 Hz, 2H). 33286 427

CH CH N-(2-Amino-phenyl)-4-[(4- methoxy-phenylamino)-methyl]- benzamide¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.64 (s, 1H), 7.97 (d, J=8.2 Hz, 2H),7.53 (d, J=8.5 Hz, 2H), 7.21 (d, J=1.4, 8.0 Hz, 1H), 7.02 (ddd, J=1.4,7.4, # 8.0 Hz, 1H), 6.83 (dd, J=1.4, 8.0 Hz, 1H), 6.74 (m, 2H), 6.65(ddd, J=1.4, 7.7, 8.8 Hz, 1H), 6.58 (m, 2H), 5.99 (t, J=6.3 Hz, 1H),4.93 (s, 2H, NH₂), 4.36 (d, J=6.0 Hz, 2H), 3.68 (s, 3H). 33 287 428

CH CH N-(2-Amino-phenyl)-4- (benzo[1,3]dioxol-5-ylaminomethyl)-benzamide¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.65 (s, 1H), 7.98 (d, J=7.9 Hz, 2H),7.52 (d, J=7.9 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H), 7.02 (dd, J=7.0, 7.0 Hz,# 1H), 6.83 (d, J=7.5 Hz, 1H), 6.63-6.69 (m, 2H), 6.33 (d, J=2.2 Hz,1H), 6.15 (t, J=6.16 Hz, 1H), 6.04 (dd, J=2.2, 8.4 Hz, 1H), 5.86 (s,2H), 4.94 (s, 2H, NH₂), 4.35 (d, J=6.16 Hz, 2H). 33 288 429

CH CH N-(2-Amino-phenyl)-4-[(2- methoxy-phenylamino)-methyl]- benzamide¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.63 (s, 1H), 7.90 (d, J=8.2 Hz, 2H),7.52 (d, J=8.2 Hz, 2H), 7.22 (d, J=7.7 Hz, 1H), 7.02 (ddd, J=1.4, 7.1,8.0 # Hz, 1H), 6.86 (m, 2H), 6.56-6.75 (m, 3H), 6.43 (dd, J=1.6, 7.7 Hz,1H), 5.75 (t, J=6.3 Hz, 1H), 4.93 (s, 2H, NH₂), 4.47 (d, J=6.3 Hz, 2H),3.88 (s, 3H). 33 289 430

CH CH N-(2-Amino-phenyl)-4-[(3- methoxy-phenylamino)-methyl]- benzamide¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.61 (s, 1H), 7.98 (d, J=8.0 Hz, 2H),7.53 (d, J=8.2 Hz, 2H), 7.21 (dd, J=1.1, 7.7 Hz, 1H), 6.97-7.05 (m, 2H),6.82 # (dd, J=1.2, 8.1 Hz, 1H), 6.46 (ddd, J=1.4, 7.7, 8.0 Hz, 1H), 6.41(t, J=6.3 Hz, 1H), 6.16-6.25 (m, 3H), 4.93 (s, 2H, NH₂), 4.39 (d, J=6.0Hz, 2H), 3.69 (s, 3H). 33 290 431

CH CH N-(2-Amino-phenyl)-4-(2,2,2- trifluoro-acetylamino)-benzamide ¹HNMR (300 MHz, DMSO-d₆) δ (ppm): 11.53 (s, 1H), 9.71(s, 1H), 8.08 (d,J=8.2 Hz, 2H), 7.86 (d, J=8.8 Hz, 2H), 7.23 (d, J=7.6 Hz, 1H), 7.03 (dd,# J=7.0, 7.6 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.66 (dd, J=7.0, 7.6 Hz,1H), 4.96 (s, 2H, NH₂). 14 291 432

CH CH N-(2-Amino-phenyl)-4-{[4-chloro- 6-(3,4,5-trimethoxy-benzylamino)-pyrimidin-2-ylamino]- methyl}-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 9.64 (s, 1H), 7.95 (d, J=7.5 Hz, 2H), 7.70 (bs, 2H), 7.45 (d,J=8.4 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.03 (dd, # J=7.0, 7.5 Hz, 1H),6.84 (d, J=7.9, Hz, 1H), 6.60-6.72 (m, 3H), 5.87 (s, 1H), 4.93 (s, 2H,NH₂), 4.54 (d, J=6.2 Hz, 2H), 4.43 (bs, 2H), 3.78 (s, 6H), 3.68 (s, 3H).24, 33 292 433

CH CH N-(2-Amino-phenyl)-4-{[4-chloro- 6-(3,4,5-trimethoxy-phenylamino)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 9.65 (s, 1H), 9.43 (s, 1H), 7.97 (m, 3H), 7.46 (bs, 2H), 7.21 (d,J=7.5 Hz, 1H), 7.02 (m, 3H), 6.83 (d, J=7.0 Hz, # 1H), 6.65 (dd, J=7.5,7.5 Hz, 1H), 6.08 (s, 1H), 4.93 (s, 2H, NH₂), 4.69 (bs, 2H), 3.65 (s,9H). 24, 33 293 434

CH CH N-(2-Amino-phenyl)-4-(3,4- dimethoxy-benzylamino)- benzamide ¹HNMR (300 MHz, DMSO-d₆) δ (ppm): 9.31 (s, 1H), 7.79 (d, J=8.8 Hz, 2H),7.19 (d, J=7.9 Hz, 2H), 7.04 (s, 1H), 6.92-7.01 (m, 3H), 6.80-6.87 (m,2H), 6.69 # (d, J=8.8 Hz, 2H), 6.62 (m, 1H), 4.87 (s, 2H, NH₂), 4.32 (d,J=5.7 Hz, 2H), 3.80 (s, 3H), 3.78 (s, 3H). 33 294 435

CH CH N-(2-Amino-phenyl)-4-[(4- morpholin-4-yl-pyrimidin-2-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.64 (s,1H), 7.95 (d, J=8.4 Hz, 2H), 7.87 (d, J=7.9 Hz, 1H), 7.47 (d, J=7.9 Hz,2H), 7.31 (bs, 1H), 7.21 (d, J=7.5, 1H), 7.02 (dd, J=7.9 Hz, 1H), 6.83(d, J=7.9 Hz, # 1H), 6.65 (dd, J=7.0, 7.0 Hz, 1H), 6.09 (d, J=6.2 Hz,1H), 4.94 (s, 2H, NH₂), 4.54 (d, J=5.7 Hz, 2H), 3.67 (s, 4H), 3.53 (s,4H). 24, 1, 33 295 436

CH CH N-(2-Amino-phenyl)-4-{[2-(1H- indol-3-yl)-ethylamino]-methyl}-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 10.82 (s, 1H), 9.65 (s,1H), 7.98 (d, J=8.4 Hz, 2H), 7.56 (d, J=7.9 Hz, 1H), 7.51 (d, J=8.4 Hz,2H), 7.38 (d, J=7.9 Hz, 2H), 7.18-7.23 (m, 2H), 7.11 (dd, J=7.0, # 8.0Hz, 1H), 7.01 (m, 2H), 6.83 (d, J=7.9 Hz, 1H), 6.51 (dd, J=7.5, 6.6 Hz,1H), 4.93 (s, 2H, NH₂), 3.89 (s, 2H), 2.89 (m, 4H). 57 296 437

CH CH N-(2-Amino-phenyl)-4-[(4- methylsulfanyl-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.67 (s, 1H), 7.99(d, J=7.5 Hz, 2H), 7.52 (d, J=7.5 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H), 7.13(d, J=7.5 Hz, 2H), 7.03 (dd, # J=7.5, 7.5 Hz, 1H), 6.83 (d, J=7.9 Hz,1H), 6.53 (m, 4H), 4.95 (s, 2H, NH₂), 4.41 (d. J=5.7 Hz, 2H), 2.37 (s,3H). 33 297 438

CH CH N-(2-Amino-phenyl)-4-[(3- methylsulfanyl-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.66 (s, 1H), 7.99(d, J=7.5 Hz, 2H), 7.53 (d, J=7.5 Hz, 2H), 7.21 (d, J=7.5 Hz, 1H), 7.03(m, 2H), 6.83 (d, J=7.9 Hz, # 1H), 6.65 (dd, J=7.5, 7.5 Hz, 1H),6.39-6.51 (m, 4H), 4.94 (s, 2H, NH₂), 4.41 (d. J=5.7 Hz, 2H), 2.42 (s,3H). 33 298 439

CH CH N-(2-Amino-phenyl)-4-{[4-chloro- 6-(3,4-dimethoxy-phenyl)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 9.66 (s, 1H), 8.37 (s, 1H), 7.99 (d, J=7.5 Hz, 2H), 7.68-7.79 (m,2H), 7.55 (bs, 2H), 7.37 (s, 1H), 7.20 (d, J=7.1 Hz, 1H), 7.11 # (bs,1H), 7.02 (dd, J=7.5, 7.5 Hz, 1H), 6.82 (d, J=7.9 Hz, 1H), 6.64 (dd,J=7.5, 7.5 Hz, 1H), 4.93 (s, 2H, NH₂), 4.86 (s, 2H), 3.88 (s, 6H). 15,33 299 440

CH CH N-(2-Amino-phenyl)-4-{[4-(3,4- dimethoxy-phenyl)-pyrimidin-2-ylamino]-methyl}-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.64 (s,1H), 8.35 (d, J=4.8 Hz, 1H), 7.97 (d, J=7.9 Hz, 2H), 7.89 (m, 1H), 7.72(m, 2H), 7.55 (d, J=7.5 Hz, 2H), 7.2 # (d, J=5.3 Hz, 2H), 7.10 (d, J=8.4Hz, 1H), 7.01 (m, 1H), 6.82 (d, J=7.0 Hz, 1H), 6.41 (t, J=7.5 Hz, 1H),4.92 (s, 2H, NH₂), 4.68 (d, J=6.2 Hz, 2H), 3.82 (s, 6H). 15, 1, 33 300441

CH CH 4-[(2-Acetyl-4,5-dimethoxy- phenylamino)-methyl]-N-(2-amino-phenyl)-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.68 (s, 1H),9.45 (t, J=5.7 Hz, 1H), 8.01 (d, J=7.9 Hz, 2H), 7.54 (d, J=8.4 Hz, 2H),7.32 (s, 1H), 7.21 (d, J=7.5 Hz, 1H), 7.02 (dd, J=6.6, # 7.5 Hz, 1H),6.83 (d, J=7.5 Hz, 1H), 6.65 (dd, J=7.0, 7.5 Hz, 1H), 6.31 (s, 1H), 4.95(s, 2H, NH₂), 4.63 (d, J=5.7 Hz, 2H), 3.78 (s, 3H), 3.76 (s, 3H). 33 301442

CH CH N-(2-Amino-phenyl)-4-{[4-(3,4- dimethoxy-phenylamino)-pyrimidin-2-ylamino]-methyl}- benzamide ¹H NMR (300 MHz, CD₃OD + CDCl₃)δ (ppm): 7.99 (d, J=7.9 Hz, 2H), 7.80 (d, J=6.2 Hz, 1H), 7.76 (s, 1H),7.52 (d, J=8.4 Hz, 2H), 7.27 (m, 1H), 7.14 (m, 1H), 7.05 (dd, # J=2.2,8.8 Hz, 1H), 6.95 (d, J=7.9 Hz, 1H), 6.88 (d, J=8.8 Hz, 1H), 6.83 (d,J=7.9 Hz, 1H), 6.08 (d, J=6.2 Hz, 1H), 4.75 (s, 2H), 3.79 (s, 3H), 3.42(s, 3H). 1, 33 302 443

CH CH N-(2-Amino-phenyl)-4-{[[2-(tert-butyl-dimethyl-silanyloxy)-ethyl]- (3,4-dimethoxy-phenyl)-amino]-methyl}-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.66 (s, 1H), 7.96(d, J=8.4 Hz, 2H), 7.42 (d, J=7.9 Hz, 2H), 7.20 (d, J=7.5 Hz, 1H), 7.02((dd, J=6.6, 8.4 Hz, 1H), 6.83 # (d, J=7.0 Hz, 1H), 6.77 (d, J=8.8 Hz,1H), 6.65 (dd, J=7.0, 7.0 Hz, 1H), 6.44 (d, J=2.6 Hz, 1H), 6.19 (dd,J=2.6, 8.8 Hz, 1H), 4.93 (s, 2H), 4.67 (s, 2H), 3.88 (t, J=5.7 Hz, 2H),3.71 (s, 3H), 3.67 (s, 3H), 3.60 (t, J=5.5 Hz), 0.96 (s, 9H), 0.06 (s,6H). 33 303 444

CH CH N-(2-Amino-phenyl)-4-{[(3,4- dimethoxy-phenyl)-(2-hydroxy-ethyl)-amino]-methyl}-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm) δ(ppm): 9.65 (s, 1H), 7.96 (d, J=7.5 Hz, 2H), 7.42 (d, J=7.5 Hz, 2H),7.21 (d, J=7.5 Hz, 1H), 7.02 ((dd, J=7.0, 7.5 Hz, 1H), 6.83 (d, J=7.9Hz, 1H), # 6.78 (d, J=8.8 Hz, 1H), 6.65 (dd, J=7.0, 7.5 Hz, 1H), 6.44(s, 1H), 6.19 (d, J=8.8 Hz, 1H), 4.94 (s, 2H), 4.79 (m, 1H), 4.66 (s,2H), 3.67 and 3.71 (2s and broading underneath, 8H), 3.55 (m, 2H). 33,23 304 445

CH N N-(2-Amino-phenyl)-6-[(3,4,5- trimethoxy-phenylamino)-methyl]-nicotinamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.82 (s, 1H), 9.13 (s,1H), 8.33 (d, J=8.0 Hz, 1H), 7.56 (d, J=8.5 Hz, 1H), 7.21 (d, J=7.7 Hz,1H), 7.03 ((dd, J=7.4, 7.7 Hz, 1H), 6.82 (d, J=8.0 Hz, 1H), # 6.40 (dd,J=7.4, 7.7 Hz, 1H), 6.31 (t, J=5.8 Hz, 1H), 5.96 (s, 2H), 5.01 (s, 2H),4.48 (d, J=5.8 Hz, 2H), 3.70 (s, 6H), 3.56 (s, 3H). 33 305 446

CH N N-(2-Amino-phenyl)-6-[2-(4-oxo- 4H-quinazolin-3-yl)-ethylamino]-nicotinamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 8.69 (d, J=2.2 Hz, 1H),8.46 (s, 1H), 8.40 (d, J=8.8 Hz, 1H), 8.32-8.36 (m, 1H), 7.91-7.96 (m,1H), 7.77 (m, # 1H), 7.67 (m, 1H) 7.5 (m, 4H), 7.2 (s, 1H), 4.46 (t,J=5.9 Hz, 1H), 4.09 (t, J=5.9 Hz, 2H).  3 306 447

CH CH N-(2-Amino-phenyl)-4-[bis- (3-trifluoromethoxy-benzyl)-amino]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.37 (s, 1H), 7.84(d J=8.8 Hz, 2H), 7.54 (dd, J=7.9, 7.9 Hz, 2H), 7.18-7.37 (m, 6H), 7.17(d, J=7.0 Hz, 1H), 6.99 # (dd, J=7.0, 7.9 Hz, 1H), 6.82 (m, 3H), 6.63(dd, J=7.5, 7.5 Hz, 1H), 4.94 (s, 4H), 4.86 (s, 2H). 33 307 448

CH CH N-(2-Amino-phenyl)-4-[(2- dimethylamino-benzothiazol-5-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.58 (s,1H), 7.92 (d, J=7.9 Hz, 2H), 7.49 (d, J=7.9 Hz, 2H), 7.34 (d, J=8.8 Hz,1H), 7.15, (d, J=7.5 Hz, # 1H), 6.96 (t, J=7.9 Hz, 1H), 6.76 (d, J=7.9Hz, 1H), 6.59 (d, J=7.5 Hz, 1H), 6.55 (s, 1H), 6.44 (d, J=8.4 Hz, 1H),6.34 (t, J=5.7 Hz, 1H), 4.88 (bs, 2H), 4.37 (d, J=5.7 Hz, 2H), 3.06 (s,6H). 33 308 449

CH CH N-(2-Amino-phenyl)-4-[(2-oxo- 2,3-dihydro-1H-benzoimidazol-5-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 10.2 (s,1H), 10.1 (s, 1H), 9.62 (s, 1H), 7.94 (d, J=7.9 Hz, 2H), 7.41 (d, J=7.9Hz, 2H), 7.15 (d, J=7.5 # Hz, 1H), 6.96 (t, J=7.5 Hz, 1H), 6.77 (d,J=7.9 Hz, 1H), 6.69 (d, J=8.4 Hz, 1H), 6.59 (t, J=7.5 Hz, 1H), 6.34 (d,J=8.4 Hz, 1H), 6.34 (t, J=8.4 Hz, 1H), 6.30 (s, 1H), 4.89 (bs, 2H), 4.72(s, 2H). 33 309 450

CH CH N-(2-Amino-phenyl)-4-[(4- trifluoromethylsulfanyl-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.60(s, 1H), 7.94 (d, J=7.9 Hz, 2H), 7.46 (d, J=7.9 Hz, 2H), 7.35 (d, J=8.4Hz, 2H), 7.15 (d, J=7.9 # Hz, 1H), 7.11 (d, J=6.2 Hz, 1H), 6.97 (t,J=7.0 Hz, 1H), 6.77 (d, J=7.5 Hz, 1H), 6.66 (d, J=8.4 Hz, 2H), 6.60 (t,J=7.9 Hz, 1H), 4.88 (bs, 2H), 4.72 (d, J=6.2 Hz, 2H). 33 310 451

CH CH N-(2-Amino-phenyl)-4-{[2- (pyridin-3-ylmethylsulfanyl)-1H-benzoimidazol-5-ylamino]- methyl}-benzamide ¹H NMR (300 MHz, CD₃OD) δ(ppm): 8.67 (d, J=1.8 Hz, 1H), 8.47 (dd, J=1.3, 4.4 Hz, 1H), 8.08 (s,1H), 8.03 (d, J=7.9 Hz, 2H), 7.92 (d, # J=8.4 Hz, 1H), 7.87 (d, J=7.9Hz, 2H), 7.58 (d, J=8.4 Hz, 1H), 7.36-7.30 (m, 3H); 7.20-7.15 (m, 1H);7.08 (dt, J=1.3, 8.4 Hz, 1H), 6.94 (dd, J=1.3, 7.9 Hz, 1H), 6.77 (d,J=2.2 Hz, 1H), 6.74 (d, J=2.2 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 4.55 (s,2H); 4.20 (bs, 2H); 3.36 (s, 2H). 33 311 452

CH CH N-(2-Amino-phenyl)-4-{[2- (pyridin-3-ylmethylsulfanyl)-benzooxazol-5-ylamino]-methyl}- benzamide ¹H NMR (300 MHz, CD₃OD) δ(ppm): 8.60 (s, 1H), 8.36 (d, J=4.4 Hz, 1H), 7.89 (d, J=7.9 Hz, 2H),7.87 (m, 1H); 7.47 (d, J=7.9 Hz, 2H), 7.30 (t, # J=6.6 Hz, 1H),7.20-7.15 (m, 2H); 7.04 (t, J=7.5 Hz, 1H), 6.87 (d, J=7.9 Hz, 1H), 6.73(t, J=7.5 Hz, 1H), 6.66 (s, 1H); 6.61 (d, J=8.8 Hz, 1H), 4.87 (s, 2H);4.45 (s, 2H); 4.37 (s, 2H); 3.35 (s, 2H). 33 312 453

N-(2-Amino-5-trifluoromethyl- phenyl)-4-[(3,4-dimethoxy-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, CDCl₃) δ (ppm): 8.21 (s,1H); 7.90 (d, J=8.4 Hz, 2H); 7.54 (m, 1H); 7.50 (d, J=8.4 Hz, 2H);7.41-7.34 (m, 2H); 6.87 (d, J=8.4 Hz, # 1H); 7.77 (d, J=8.4 Hz, 1H);6.35 (d, J=2.2 Hz, 1H); 6.20 (dd, J=2.2, 8.8 Hz, 1H); 4.43 (s, 2H); 4.29(s, 2H); 3.84 (s, 6H). 33 313 454

N-(2-Amino-4,5-difluoro-phenyl)- 4-[(3,4-dimethoxy-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, CDCl₃) δ (ppm): 8.21 (s, 1H); 7.84(d, J=7.9 Hz, 2H); 7.45 (d, J=7.9 Hz, # 2H); 7.20 (dd, J=2.6, 8.4 Hz,1H); 6.76 (d, J=8.8 Hz, 1H); 6.57 (dd, J=3.9, 7.9 Hz, 1H); 6.32 (d,J=2.6 Hz, 1H); 6.16 (dd, J=2.6, 8.4 Hz, 1H); 4.40 (s, 2H); 3.82 (s, 9H).33 314 455

CH CH N-(2-Amino-phenyl)-4-[(2-oxo- 2,3-dihydro-benzooxazol-5-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.60 (s,1H); 7.93 (d, J=7.9 Hz, 2H); 7.47 (d, J=7.9 Hz, 2H); 7.16 (d, J=7.5 Hz,# 1H); 6.97 (m, 2H); 6.78 (d, J=7.5 Hz, 1H); 6.59 (t, J=7.5 Hz, 1H);6.35 (t, J=5.7 Hz, 1H); 6.27 (m, 2H); 4.88 (bs, 2H); 4.34 (d, J=6.2 Hz,2H). 33 315 456

CH CH N-(2-Amino-phenyl)-4-[(2- methylamino-benzothiazol-5-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 7.92 (d,J=7.9 Hz, 2H), 7.66 (d, J=4.4 Hz, 1H), 7.49 (d, J=7.9 Hz, 2H), 7.26 (d,J=8.4 Hz, 1H), 7.15 (d, # J=7.9 Hz, 1H), 6.96 (d, J=8.4 Hz, 1H), 6.59(t, J=7.9 Hz, 1H), 6.53 (s, 1H), ); 6.40 (dd, J=1.3, 8.4 Hz, 1H); 6.28(t, J=5.7 Hz, 1H), 4.88 (bs, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.85 (d, J=4.4Hz, 3H). 33 316 457

N-(2,6-Diamino-phenyl)-4-[(3,4- dimethoxy-phenylamino)-methyl]-benzamide ¹H NMR (300 MHz, CDCl₃) δ (ppm): 8.09 (s, 1H); 7.88 (d, J=7.5Hz, 2H); 7.48 (d, J=7.5 Hz, 2H); 6.97 (d, J=7.9 Hz, 1H); 6.73 (d, J=8.4Hz, 2H); # 6.64 (d, J=7.9 Hz, 1H); 6.29 (s, 1H); 6.14 (d, J=8.4 Hz, 1H);4.39 (s, 2H); 3.81 (s, 3H); 3.80 (s, 3H); 3.70 (bs, 5H). 33 317 458

CH CH N-(2-Amino-phenyl)-4-{[2- (2-methoxy-ethyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-ylamino]- methyl}-benzamide ¹H NMR (300 MHz,DMSO-d₆) δ (ppm): 9.61 (s, 1H); 7.95 (d, J=7.9 Hz, 2H); 7.73 (t, J=5.7Hz, 1H); 7.52 (d, J=8.4 Hz, 1H); 7.47 (d, # J=7.9 Hz, 2H); 7.15 (d,J=7.9 Hz, 1H); 6.97 (d, J=7.5 Hz, 1H); 6.92 (bs, 1H); 6.86 (d, J=8.4 Hz,1H); 6.77 (d, J=7.9 Hz, 1H); 6.59 (t, J=7.5 Hz, 1H); 4.89 (bs, 2H); 4.54(d, J=5.7 Hz, 2H); 3.65 (t, J=5.3 Hz, 2H); 3.47 (t, J=5.3 Hz, 2H); 3.20(s, 3H); 33 318 459

CH CH N-(2-Amino-phenyl)-4-{(3- spiro[1′,2′]dioxolane-1-methyl-2-oxo-2,3-dihydro-1H-indol-5- ylamino)-methyl}-benzamide ¹H NMR (300MHz, DMSO-d₆) δ (ppm): 9.59 (s, 1H); 7.92 (d, J=8.3 Hz, 2H); 7.46 (d,J=8.3 Hz, 2H); 7.15 (d, J=7.5 Hz, 1H); 6.96 (t, J=7.0 Hz, # 1H);6.78-6.71 (m, 3H); 6.62-6.54 (m, 2H); 6.26 (t, J=7.5 Hz, 1H); 4.87 (s,2H); 4.36-4.32 (m, 4H); 4.23-4.19 (m, 2H); 2.98 (s, 3H). 33 319 460

CH N N-(2-Amino-phenyl)-6-(2- phenylamino-ethylamino)- nicotinamide ¹HNMR (300 MHz, CD₃OD) δ (ppm): 8.67 (d, J=2.2 Hz, 1H), 7.97 (dd, J=2.5,8.9 Hz, 1H), 7.58 (m, 1H); 7.51 (m, 1H); 7.15 (dd, J=1.1, 7.7 Hz, 1H),7.08 # (m, 2H); 6.89 (dd, J=1.4, 8.0 Hz, 1H), 6.76 (dt, J=4.4, 7.7 Hz,1H), 6.67 (d, J=7.7 Hz, 2H), 6.60 (m, 2H); 4.87 (bs, 2H); 3.60 (t, J=6.3Hz, 2H), 3.35 (t, J=6.3 Hz, 2H). 33 320 461

CH CH N-(2-Amino-phenyl)-4-[(1,3- dimethyl-2,4-dioxo-1,2,3,4-tetrahydro-quinazolin-6-ylamino)- methyl]-benzamide ¹H NMR (300 MHz,DMSO-d₆) δ (ppm): 9.59 (s, 1H); 7.92 (d, J=7.9 Hz, 2H); 7.47 (d, J=7.9Hz, 2H); 7.22 (d, J=8.8 Hz, 1H); # 7.16-7.09 (m, 3H); 6.96 (t, J=7.5 Hz,1H); 6.76 (d, J=7.9 Hz, 1H); 6.65-6.56 (m, 2H); 4.87 (s, 2H); 4.42 (d,J=5.3 Hz, 2H); 3.44 (s, 3H); 3.26 (s, 3H). 33 321 462

CH CH N-(2-Amino-phenyl)-4-[(6-methyl- 6H-ir,dolo[2,3-b]quinoxalin-9-ylamino)-methyl]-benzamide ¹H NMR (300 MHz, DMSO-d₆) δ (ppm): 9.60 (s,1H); 8.19 (d, J=8.4 Hz, 1H); 8.05 (d, J=8.4 Hz, 1H); 7.95 (d, J=7.9 Hz,2H); # 7.76 (t, J=7.0 Hz, 1H); 7.65 (t, J=7.9 Hz, 1H); 7.57 (d, J=7.9Hz, 2H); 7.54 (d, J=8.8 Hz, 1H); 7.41 (d, J=1.3 Hz, 1H); 7.22 (dd,J=1.8, 8.8 Hz, 1H); 7.14 (d, J=7.9 Hz, 1H); 6.95 (t, J=7.5 Hz, 1H); 6.76(t, J=7.9 Hz, 1H); 6.57 (t, J=7.5 Hz, 1H); # 6.51 (bs, 1H); 4.86 (bs,2H); 4.54 (d, J=4.8 Hz, 2H); 3.85 (s, 3H). 33 322 463

N CH N-(2-Amino-phenyl)-6-(1-hydroxy- cyclohexylethynyl)-nicotinamideLRMS calc: 335.40, found: 336.1 (MH)⁺ 14, 3 323 464

N CH N-(2-Amino-phenyl)-6-p- tolylsulfanyl-nicotinamide LRMS calc:335.42, found: 336.1 (MH)⁺ 14, 3 324 465

CH CH N-(2-Amino-phenyl)-4-[5-(indan- 2-ylaminomethyl)-thiophen-2-ylmethyl]-benzamide LRMS calc: 453.6, found: 454.2 (MH)⁺ 21 325 466

CH CH N-(2-Amino-phenyl)-4-[5-(pyridin- 2-ylaminomethyl)-thiophen-2-ylmethyl]-benzamide LRMS calc: 414.52, found: 415 (MH)⁺ 21 326 467

CH CH N-(2-Amino-phenyl)-4-[(5-bromo- thiazol-2-ylamino)-methyl]-benzamide LRMS calc: 403.3, found: 404 (MH)⁺ 21 327 468

CH CH N-(2-Amino-phenyl)-4-[(5-phenyl- 1H-pyrazol-3-ylamino)-methyl]-benzamide LRMS calc: 483.45, found: 484.1 (MH)⁺ 21

[0459] TABLE 4c Characterization of Additional Compounds Ex. CpdCompound Name Characterization Schm 426 571

N-(2-Hydrox-phenyl)-4-[(3,4,5-tri- methoxy-phenyl- amino)-methyl]-benza-mide ¹H NMR(DMSO-d₆): δ9.57(brs, 1H), 7.98(d, J=8.3Hz, 2H), 7.75(d,J=7.5Hz, 1H), 7.57(d, J=8.3Hz, 2H), 7.07(t, J=8.3Hz, 1H), 6.95(d,J=7.0Hz, 1H), 6.85(t, J=7.9Hz, 1H), 6.21(t, J=6.1Hz, 1H), 5.95 (s, 2H),4.38(d, J=5.7Hz, 2H), #3.70(s, 6H), 3.56(s, 3H). 33, 55 427 572

N-(2-hydroxy-phenyl)-4-[(3,4-Di- methoxy-phenyl- amino)-methyl]-benza-mide ¹H NMR(300MHz, DMSO-D₆)δ(ppm): 9.9(bs, 1H), 9.53(s, 1H), 7.97(d,J=7.9Hz, 2H), 7.73(d, J=7.5Hz, 1H), 7.55(d, J=7.9Hz, 2H), 7.08(dd,J=7.5, 7.5Hz, 1H), 6.96(d, J=7.9Hz, 1H), 6.88(dd, J=7.5, 7.5Hz, 1H),6.72(d, J=8.8Hz, 1H), 6.38(s, #1H), 6.05 (m, 2H), 4.36(d, J=5.7Hz, 2H),3.72(s, 3H), 3.65(s, 3H). 33, 55 428 573

N-(4-Amino-thiophen-3-yl)-4-{[6-(2-morpho- lin-4-yl-eth-oxy)-benzothiazol-2-yla- mino]-methyl}-benza- mide ¹H NMR:(Acetone-d₆)δ(ppm): 9.09(bs, 1H), 8.03(d, J=7.9Hz, 2H), 7.96(d, J=7.5Hz,1H), 7.65(d, J=7.9Hz, 2H), 7.61(d, J=3.5Hz, 1H), 7.51(bs, 2H), 7.41(d,J=8.8Hz, 1H), 7.36(s, 1H), 6.95(d, J=6.2Hz, #1H), 6.35(d, J=3.5Hz, 1H),4.85(s, 2H), 4.20(t, J=5.7Hz, 2H), 3.69)t, J=4.4Hz, 4H), 2.87-2.81(m,2H), 2.62-2.57 (m, 4H). 33, 60 429 574

N-(4-Amino-thiophen-3-yl)-4-[(3,4,5-tri- methoxy-phenyl-amino)-methyl]-benzamide ¹H NMR(DMSO-d₆): δ9.66(brs, 1H), 7.94(d,J=7.5Hz, 2H), 7.56(d, J=7.9Hz, 2H), 6.22-6.16(m, 1H), 5.94(s, 2H),4.91(s, 2H), 4.38(d, J=5.7Hz, 4H), 3.70 (s, 6H), 3.55(s, 3H). 33, 60 430575

N-(4-Amino-thiophen-3-yl)-4-(5-meth- oxy-1H-benzo-imidazol-2-ylsulfanyl- methyl)-benzamide (DMSO)δ(ppm): 12.43(bs, 1H),9.59(bs, 1H), 7.84(d, J=8.1Hz, 2H), 7.56(d, J=8.1Hz, 2H), 7.48(d,J=3.7Hz, 1H), 7.32(bs, 1H, SCH), 6.96(bs, 1H, SCH), 6.74(dd, J=8.8,2.2Hz, 1H), 6.11(d, J=3.7Hz, 1H), 4.84(s, 2H), 4.59(s, 2H), 3.76(s,#3H). LRMS: 410.1(calc)(M); 411.2(found)(M + H)+ 36, 60 431 576

2-{4-(4-Methoxy-benzyl- amino)-phenyl]-cyclo- propanecarboxylicacid(2-amino-phenyl)-amide ¹H-NMR(DMSO-d6), δ(ppm): 9.22(bs, 1H),8.19(bs, 1H), 7.63(d, J=7.1Hz, 1H), 7.53(t, J=4.2Hz, 1H), 7.41 (dd,J=9.2, 1.5Hz, 1H), 7.25(d, J=8.3Hz, 2H), 7.06(d, J=7.1Hz, 1H), 6.85(d,J=8.3Hz, 2H), 6.62-6.59(m, 3H), 4.51 #(d, J=4.2Hz, 2H), 3.78(s, 3H),2.77(d, J=3.1Hz, 1H), 2.45(d, J=1.1Hz, 1H), 1.22(m, 1H), 1.05(m, 1H).432 577

N-(2-Amino-phenyl)-4-(3-cya- no-6-methyl-pyridin-2-yloxy-methyl)-benzamide ¹H NMR(DMSO-d₆)δ(ppm): 9.72(brs, 1H), 8.23(d, J=7.5Hz,1H), 8.06(d, J=7.9Hz, 2H), 7.67(d, J=7.9Hz, 2H), 7.23(d, J=7.9Hz, 1H),7.15(d, J=7.9Hz, 1H), 7.03(t, J=7.5Hz, 1H), 6.84(d, J=7.9Hz, 1H),6.65(t, J=7.5hz, 1H), 5.62(brs, 2H), 4.97(brs, 2H) 11 433 578

N-(2-Amino-phenyl)-4-{[4-(6-meth- oxy-pyridin-3-yl)-py-rimidin-2-ylamino]-meth- yl}-benzamide ¹H NMR(300MHz, DMSO-D₆)δ(ppm):9.63(s, 1H), 8.95(d, J=2.2Hz, 1H), 8.40(d, J=5.3Hz, 2H), 7.96 (m, 3H),7.54(d, J=7.5Hz, 2H), 7.22(dd, J=5.3, 7.8Hz, 2H), 7.01(m, 2H), 6.83(d,J=7.5Hz, 1H), 6.64 (dd, J=7.0, 7.9Hz, 1H), 4.92 #(s, 2H), 4.70(d,J=6.2Hz, 2H), 3.98(s, 3H). 15, 33 434 579

2-Acetyl- amino-5-[4-(2-amino- phenylcarba- moyl)-benzyl]-thiophene-3-car- boxamide ¹H NMR: (DMSO)δ(ppm): 11.98(bs, 1H),9.61(bs, 1H), 7.93(d, J=8.1Hz, 2H), 7.81(s, 1H), 7.45(s, 1H), 7.38(d,J=8.1Hz, 1H), 7.19(s, 1H), 7.16(d, J=7.3Hz, 1H), 6.97(dd, J=7.0, 7.0Hz,1H), 6.77(d, J=7.3Hz, 1H), 6.59(dd, J=7.3, 7.3Hz, 1H), #4.88(bs, 2H),4.10(s, 2H), 2.15(s, 3H). 49 435 580

N-(2-Amino-phenyl)-4-[(3-meth- yl-2-methyl- amino-3H-benzo-imidazol-3H-benzo- imidazol-5-ylamino)-meth- yl]-benzamide ¹HNMR(DMSO)δ(ppm): 9.56(s, 1H), 7.90(d, J=7.9Hz, 2H), 7.49(d, J=7.9Hz,2H), 7.15(d, J=7.5Hz, 1H), 6.95(t, J=7.5Hz, 1H), 6.78(dd, J=13.2,8.35Hz, 2H), 6.58(t, J=7.5Hz, 1H), 6.39(s, #1H), 6.31 (m, 2H), 5.75(t,J=6.15Hz, 1H), 4.87(s, 2H), 4.32(d, J=5.7Hz, 2H), 3.34(s, 3H), 2.82(d,J=8.5Hz, 3H). 61 438 591

5-(5-Methoxy-1H-benzo- imidazol-2-ylsulfanyl- methyl)-benzo-furan-2-carboxylic acid(2-a- mino-phenyl)amide ¹H NMR(DMSO)δ(ppm):9.84(s, 1H), 7.84(s, 1H), 7.67(s, 1H), 7.63(d, J=8.5Hz, 1H), 7.55(d,J=9.0Hz, 1H), 7.17(d, J=8.0Hz, 1H), 6.97(t, J=7.5Hz, 1H), 6.78(d,J=8.0Hz, 1H), 6.78-6.74(m, #3H), 6.59(t, J=7.5Hz, 1H), 5.71(s, 2H),4.94(s, 1H), 4.65(s, 2H), 3.76(s, 3H). 64 439 592

5-(3,4,5-Trimethoxy-benzyl- amino)-benzo- furan-2-carboxylicacid(2-amino-phenyl)-amide ¹H NMR(DMSO)δ(ppm): 9.69(s, 1H), 7.47(s, 1H),7.41(d, J=8.8Hz, 1H), 7.19(d, J=6.6Hz, 1H), 6.97 (dd, J=7.5, 7.5Hz, 1H),6.89(dd, J=8.8, 2.2Hz, 1H), 6.79-6.78(m, 2H), 6.74(s, 2H), 6.60(dd,J=7.5, 7.5Hz, 1H), 6.14(t, J=5.7Hz, #1H), 4.92(s, 2H), 4.21(d, J=5.7Hz,1H), 3.75(s, 6H), 3.31(s, 3H). 64

[0460]

Example 122

[0461] Step 1:{2-[(3′-Formyl-biphenyl-4-carbonyl)-amino]-phenyl}-carbamic acidtert-butyl ester (185)

[0462] Following the procedure described in Example 15, step 1, butsubstituting 184 for 140, the title compound 185 was obtained in 74%yield. ¹H NMR (CDCl₃): δ10.10 (s, 1H), 9.41(s, 1H), 8.13 (m, 1H), 8.07(d, J=8.4 Hz, 2H), 7.89 (m, 2H), 7.77 (m, 1H), 7.70 (d, J=8.4 Hz, 2H),7.64 (m, 1H), 7.27-7.09 (m, 3H), 7.03 (s, 1H), 1.52 (s, 9H).

[0463] Step 2:N-(2-Aminophenyl)-4-[3-(indan-2-ylaminomethyl)phenyl)]-benzamide (186)

[0464] To a stirred solution of biphenyl aldehyde (104 mg, 0.25 mmol)and 2-aminoindane (33.3 mg, 0.25 mmol) in dichloroethane (1 mL) wasadded sodium triacetoxyborohydride (80 mg, 0.375 mmol) followed by aglacial acetic acid (15 ul, 0.25 mmol), and then the mixture was stirredat room temperature for 3 h. After a removal of the volatiles, theresidue was partitioned between ethyl acetate and 10% aqueous sodiumbicarbonate solution. The combined organic layers were washed withwater, dried and concentrated. Purification by flash chromatography (10%methanol in chloroform) gave the desired Boc-monoprotected product (112mg, 84% yield) as a white solid. ¹H NMR (CDCl₃):

9.21 (s, 1H), 8.03 (d, J=8.7 Hz, 2H), 7.83 (m, 1H), 7.69 (d, J=8.7 Hz,2H), 7.65 (s, 1H), 7.54-7.38 (m, 3H), 7.28 (m, 7H), 6.82 (s, 1H), 3.95(s, 2H), 3.74 (m, 1H), 3.22 (dd, J=15.6, 6.9 Hz, 2H), 2.89 (dd, J=15.6,6.6 Hz, 2H), 1.53 (s, 9H).

[0465] Following the procedure described in Example 42, step 3, butsubstituting the previous compound for 46, the title compound 186 wasobtained in 98% yield. ¹H NMR (20% CD₃OD in CDCl₃): δ7.95 (d, J=8.4 Hz,2H), 7.65 (d, J=8.4 Hz, 2H), 7.57 (m, 1H), 7.54-6.79 (m, 11H), 3.95 (s,2H), 3.66 (m, 1H), 3.16 (dd, J=15.6, 6.9 Hz, 2H), 2.81 (dd, J=15.6, 6.6Hz, 2H).

Examples 123-126

[0466] Examples 123 to 126 (compounds 187-190) were prepared using thesame procedure as described for compound 186 in Example 122 (scheme 21).

Example 127

[0467] Step 1:{2-[4-(1-Amino-cyclohexylethynyl)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester (191)

[0468] A mixture of iodide 184 (438 mg, 1.0 mmol), Pd(PPh₃)₂Cl₂ (35 mg,0.05 mmol), triphenylphosphine (7.6 mg, 0.025 mmol), and1-ethynylcyclohexylamine (185 mg, 1.5 mmol) was stirred at roomtemperature in THF (4 mL) containing triethylamine (0.56 mL, 4.0 mmol)for 20 min. To this Cul (3.8 mg, 0.02 mmol) was added and stirringcontinued for 2 h. The reaction mixture was then diluted with ethylacetate (30 mL), washed with water, and the organic layer was dried andconcentrated. Purification by flash chromatography (10% methanol inchloroform) gave the desired product 191 (420 mg, 97% yield). ¹H NMR(CDCl₃): δ9.36 (s, 1H), 7.94 (d, J=8.4 Hz, 2H), 7.77 (d, J=7.5 Hz, 1H),7.47 (d, J=8.4 Hz, 2H), 7.25-6.85 (m, 3H), 2.10-1.30 (m. 10H), 1.51 (s,9H).

[0469] Step 2:N-(2-Aminophenyl)-4-[1-(4-methoxy-benzylamino)-cyclohexylethynyl]-benzamide(192)

[0470] Following the procedure described in Example 122, step 2, butsubstituting p-anisaldehyde for 2-aminoindane, the title compound 192was obtained in 74% yield. ¹H NMR (CDCl₃): δ8.44 (s, 1H), 7.82 (d, J=8.1Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4Hz, 2H), 7.23 (m, 1H), 7.05 (m,1H), 6.84 (d, J=8.7 Hz, 2H), 6.78 (m,2H), 3.97 (s, 2H), 3.76 (s, 3H), 2.10-1.30 (m, 10H).

Example 133

[0471] Step 1:N-[2-(t-Butyloxycarbonyl)-amino-phenyl]-4-(trimethylsilylethynyl)benzamide(197)

[0472] To a stirred solution of 184 (5.00 g, 11.41 mmol) in anhydrousTHF (100 ml) under nitrogen at 0° C. were added Pd(PPh₃)₂Cl₂ (240 mg,0.34 mmol), Cul (130 mg, 0.69 mmol), and trimethylsilylacetylene (2.10ml, 14.84 mmol), respectively. Then, anhydrous Et₃N (6.36 ml, 45.66mmol) was added dropwise. The temperature was slowly warmed up to roomtemperature over 4 h. The reaction mixture was poured into a saturatedaqueous solution of NH₄Cl, and diluted with ethyl acetate. Afterseparation, the organic layer was successively washed with sat. NH₄Cl,H₂O and brine, dried over anhydrous MgSO₄, filtered and concentrated.The crude residue was then purified by flash chromatography on silicagel (AcOEt/hexane: 20/80→50/50) to afford the title compound 197 (4.42g, 10.83 mmol, 94% yield) as a yellow powder. ¹H NMR (300 MHz, CDCl₃)δ(ppm): 9.26 (bs, 1H), AB system (δ_(A)=7.91, δ_(B)=7.55, J=8.3 Hz, 4H),7.85 (d, J=7.9 Hz, 1H), 7.32-7.13 (m, 3H), 6.70 (bs, 1H), 1.53 (s, 9H),0.28 (s, 9H).

[0473] Step 2: N-(2-Amino-phenyl)-4(trimethylsilylethynyl)benzamide(198)

[0474] Following the procedure described in Example 42, step 3, butsubstituting the previous compound for 46, the title compound 198 (70mg, 0.23 mmol) was obtained as a white solid with a major fractioncomposed of a mixture of 198 and 199. ¹H NMR (300 MHz, acetone-d₆)δ(ppm): 9.20 (bs, 1H), AB system (δ_(A)=8.07, δ_(B)=7.62, J=8.2 Hz, 4H),7.32 (d, J=7.6 Hz, 1H), 7.05 (td, J=7.6, 1.2 Hz, 1H), 6.90 (d, J=7.6 Hz,1H), 6.72 (t, J=7.3 Hz, 1H), 4.66 (bs, 2H), 0.30 (s, 9H).

[0475] Step 3: N-(2-Amino-phenyl)-4-ethynylbenzamide (199)

[0476] To a stirred solution at −20° C. of a mixture of 198 and 199 inanhydrous THF (15 ml) under nitrogen was added a solution of TBAF (1 ml,1.0 M in THF). The reaction mixture was allowed to warm up to roomtemperature over 2 h and stirred at room temperature for 18 h. Then, thereaction mixture was poured into a saturated aqueous solution of NH₄Cland diluted with ethyl acetate. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (AcOEt/hexane: 30/70) to afford thetitle compound 199 (215 mg, 0.91 mmol, 46% yield over 2 steps) as a paleyellow powder. ¹H NMR (300 MHz, acetone-d₆) δ(ppm): 9.19 (bs, 1H), ABsystem (δ_(A)=8.08, δ_(B)=7.66, J=8.5 Hz, 4H), 7.33 (d, J=7.6 Hz, 1H),7.05 (t, J=7.3 Hz, 1H), 6.91 (d, J=7.6 Hz, 1H), 6.72 (t, J=7.6 Hz, 1H),4.67 (bs, 2H), 3.88 (s, 1H).

Example 134

[0477] Step 1: N-[2(t-Butyloxycarbonyl)-amino-phenyl]-4-ethynylbenzamide(200)

[0478] To a stirred solution at −20° C. of a mixture of 199 (3.48 g,8.53 mmol) in anhydrous THF (50 ml) under nitrogen was slowly added asolution of TBAF (9.4 ml, 9.38 mmol, 1.0 M in THF). The reaction mixturewas allowed to warm up to room temperature over 2 h and stirred at roomtemperature for 4 h. Then, the reaction mixture was concentrated,diluted with ethyl acetate, and successively washed with a saturatedaqueous solution of NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄,filtered and concentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/hexane: 25/75→30/70) to afford thetitle compound 200 (2.53 g, 7.53 mmol, 88% yield) as a pale yellow foam.¹H NMR (300 MHz, CDCl₃) δ(ppm): 9.31 (bs, 1H), AB system (δ_(A)=7.94,δ_(B)=7.59, J=8.5 Hz, 4H), 7.83 (d, J=7.6 Hz, 1H), 7.30-7.10 (m, 3H),6.75 (bs, 1H), 3.23 (s, 1H), 1.53 (s, 9H).

[0479] Step 2:N-(2-amino-phenyl)-4-[3-(4-chlorophenyl)-3-morpholin-4-yl-1-propyn-1-yl]-benzamide(201)

[0480] To a stirred solution at room temperature of 200 (200 mg, 0.60mmol) in anhydrous 1,4-dioxane (5 ml) under nitrogen were added4-chlorobenzaldehyde (100 mg, 0.71 mmol), morpholine (60 μl, 0.68 mmol),and Cul (6 mg, 0.03 mmol), respectively. The reaction mixture wasbubbled with nitrogen for 5 min and warmed up to 105° C. After 18 h, thereaction mixture was allowed to cool to room temperature, diluted withethyl acetate, and successively washed with a saturated aqueous solutionof NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/hexane: 40/60) to afford the desiredcompound (193 mg, 0.35 mmol, 59% yield) as a pale yellow foam. ¹H NMR(300 MHz, CDCl₃) δ(ppm): 9.40 (bs, 1H), AB system (δ_(A)=7.96,δ_(B)=7.36, J=8.5 Hz, 4H), 7.79 (d, J=Hz, 1H), 7.59 (d, J=8.4 Hz, 4H),7.25-7.10 (m, 3H), 6.91 (s, 1H), 4.80 (s, 1H), 3.82-3.68 (m, 4H),2.69-2.58 (m, 4H), 1.53 (s, 9H).

[0481] Following the procedure described in Example 42, step 3, butsubstituting the previous compound for 46, the title compound 201 wasobtained in 67% yield. ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 9.80 (bs, 1H),AB system (δ_(A)=8.06, δ_(B)=7.71, J=8.1 Hz, 4H), AB system (δ_(A)=7.65,δ_(B) =7.52, J=8.3 Hz, 4H), 7.20 (d, J=7.9 Hz, 1H), 7.02 (t, J=7.3 Hz,1H), 6.82 (d, J=7.0 Hz, 1H), 6.64 (t, J=7.5 Hz, 1H), 5.10 (s, 1H), 4.97(bs, 2H), 3.72-3.58 (m, 4H), 2.67-2.46 (m, 4H).

Example 135

[0482] Step 1: Methyl4-(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yl-amino)-benzoic ester(203)

[0483] To a stirred solution at room temperature of 202 (2.00 g, 7.11mmol) in anhydrous THF (50 ml) under nitrogen were added i-Pr₂NEt (1.86ml, 10.66 mmol) and methyl 4-aminobenzoate (1.29 g, 8.53 mmol) or ArNH₂(1.2 equiv), respectively. The reaction mixture was then refluxed for 24h. After cooling, the reaction mixture was poured into a saturatedaqueous solution of NH₄Cl, and diluted with AcOEt. After separation, theorganic layer was successively washed with sat. NH₄Cl, H₂O and brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (AcOEt/CH₂Cl₂:2/98→5/95) to afford the title compound 203 (1.70 g, 4.30 mmol, 60%yield) as a beige powder. ¹H NMR (300 MHz, CDCl₃) δ(ppm): mixture ofrotamers, 2 AB system (δ_(A)=8.03, δ_(A′)=8.00, δ_(B)=7.70, δ_(B′)=7.61,J_(AB)=J_(A′B′)=8.8 Hz, 4H), 7.43 and 7.31 (2 bs, 1H), 7.29-7.19 (m,4H), 5.84 and 5.78 (2 d, J=7.2 and 7.7 Hz, 1H), 4.98-4.77 (2 m, 1H),3.91 and 3.90 (2 s, 3H), 3.41 (dd, J=16.1, 7.0 Hz, 2H), 2.94 and 2.89 (2dd, J=15.9, 4.9 Hz, 2H).

[0484] Step 2:4-[4-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-ylamino]-N-(2-amino-phenyl)-benzamide(204)

[0485] The title compound 204 was obtained from 203 in 3 steps followingthe same procedure as Example 1, Pathway B steps 3-5. ¹H NMR (300 MHz,acetone-d₆) δ(ppm): mixture of rotamers, 8.98 (m,1H), 8.49 and 8.28 (2m,1H), 8.10-7.92 (m, 4H), 7.35-7.14 (m, 5H), 7.03 (td, J=7.6, 1.5 Hz, 1H),6.90 (dd, J=6.6, 1.3 Hz, 1H), 6.71 (td, J=7.6, 1.3 Hz, 1H), 6.57 and6.42 (2m, 1H), 6.04 and 5.86 (2m, 2H), 4.92-4.76 (m, 1H), 4.70-4.58 (m,1H), 3.44-3.26 (m, 2H), 3.08-2.92 (m, 2H). HRMS (calc.): 452.2073,(found): 452.2062.

Example 136

[0486] Step 1: Methyl4-[(4-chloro-6-(2-indanyl-amino)-[1,3,5]triazin-2-yloxy)-methyl]-benzoicester (206)

[0487] To a stirred solution at 0° C. of 205 (2.00 g, 7.11 mmol) inanhydrous THF (50 ml) under nitrogen were added i-Pr₂NEt (1.86 ml, 10.66mmol) and methyl 4-(hydroxymethyl)benzoate (1.30 g, 7.82 mmol). Afterfew minutes, NaH (95%, 186 mg, 7.11 mmol) was added portionwise. Then,the reaction mixture was allowed to warm to room temperature. After 24h, the reaction mixture was poured into a saturated aqueous solution ofNH₄Cl, and diluted with AcOEt. After separation, the organic layer wassuccessively washed with sat. NH₄Cl, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated. The crude residue was then purified byflash chromatography on silica gel (AcOEt/CH₂Cl₂: 2/98) to afford thetitle compound 206 (2.00 g, 4.88 mmol, 69% yield) as a colorless stickyfoam. ¹H NMR (300 MHz, CDCl₃) δ(ppm): mixture of rotamers, 2 AB system(δ_(A)=8.06, δ_(A′)=8.03, δ_(B)=7.52, δ_(B′)=7.46, J_(AB)=J_(AB′)=8.5Hz, 4H), 7.26-7.17 (m, 4H), 5.94 and 5.85 (2 bd, J=7.8 Hz, 1H), 5.48 and5.39 (2 s, 2H), 4.92-4.76 (2 m, 1H), 3.94 and 3.92 (2 s, 3H), 3.39 and3.33 (2 dd, J=16.0, 7.0 Hz, 2H), 2.89 and 2.84 (2 dd, J=16.0, 4.9 Hz,2H).

[0488] Step 2:4-{[4-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yloxy]-methyl}-N-(2-amino-phenyl)-benzamide(207)

[0489] The title compound 207 was obtained from 206 in 3 steps followingthe same procedure as Example 1, Pathway B steps 3-5. ¹H NMR (300 MHz,acetone-d₆+

DMSO-d₆) δ(ppm): 9.49 (m, 1H), 8.12-8.03 (m, 2H), 7.60 (t, J=7.7 Hz,2H), 7.35 (d, J=7.1 Hz, 1H), 7.28-7.13 (m, 4H), 7.07-6.94 (m, 2H), 6.90(dd, J=7.3, 1.4 Hz, 1H), 6.70 (td, J=7.3, 1.1 Hz, 1H), 6.44 (bs, 1H),6.25 (bs, 1H), 5.47 and 5.41 (2s, 2H), 4.87-4.68 (m, 3H), 3.35-3.20 (m,2H), 3.02-2.88 (m, 2H). HRMS (calc.): 467.2070, (found): 467.2063.

Example 210 Methyl4-[(4-chloro-6-phenethyl-amino-[1,3,5]triazin-2-yl-amino)-methyl]-benzoicester (208)

[0490] The title compound 208 was obtained from 2 following the sameprocedure as in Example 1, pathway B steps 2 (R¹R²NH=phenethylamine).

[0491] Step 1: Methyl4-[(4-phenethylamino-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic ester(209)

[0492] To a degazed solution of 208 (300 mg, 0.75 mmol) in MeOH (35 mL)was added 10% Pd/C (24 mg, 0.023 mmol). The reaction mixture was stirredunder a 1 atm pressure of H₂ at room temperature for 20 h then it waspurged with N₂. The palladium was removed by filtration through celiteand the reaction mixture was concentrated. The crude residue waspurified by flash chromatography on silica gel (MeOH/CH₂Cl₂: 4/96) toafford the title compound 209 (135 mg, 0.37 mmol, 50% yield). ¹H NMR(300 MHz, CDCl₃) δ(ppm): 8.08 (d, J=8.1 Hz, 2H), 7.46 (d, J=8.1 Hz, 2H),7.50-7.15 (m, 6H), 4.85-4.65 (m, 2H), 3.98 (s, 3H), 3.82-3.62 (m, 2H),3.05-2.85 (m, 2H).

[0493] Step 2:N-(2-Amino-phenyl)-4-[(4-phenethylamino-[1,3,5]triazin-2-yl-amino)-methyl]-benzamide(210)

[0494] The title compound 210 was obtained from 209 in 2 steps followingthe same procedure as in Example 1, steps 4 and 5. ¹H NMR: (300 MHz,acetone-d₆) δ(ppm): 9.03 (s, 1H), 8.17-7.87 (m, 3H), 7.49 (dd, J=19.2,8.2 Hz, 2H), 7.32-7.03 (m, 6H), 6.99 (t, J=7.6 Hz, 1H), 6.86 (d, J=8.0Hz, 1H), 6.67 (t, J=7.4 Hz, 1H), 6.60-6.30 (m, 2H), 4.72 (t, J=6.3 Hz,1H), 4.65-4.56 (m, 1H), 3.67-3.51 (m, 2H), 2.95-2.80 (m, 2H).

Example 138

[0495] Step 1: Methyl4-[(4,6-dimethoxy-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic ester (211)

[0496] In a 75 ml sealed flask, a stirred suspension of2-chloro-4,6-dimethoxy-1,3,5-triazine (540 mg, 3.08 mmol), methyl4-(aminomethyl)benzoate.HCl 2 (689 mg, 3.42 mmol), i-Pr₂NEt (1.49 ml,8.54 mmol) in anhydrous THF (30 ml) was warmed at 80° C. for 5 h. Then,the reaction mixture was allowed to cool to room temperature, pouredinto a saturated aqueous solution of NH₄Cl, and diluted with AcOEt.After separation, the organic layer was successively washed with sat.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/CH₂Cl₂: 10/90→30/70) to afford thetitle compound 211 (870 mg, 2.86 mmol, 93% yield) as a white solid. ¹HNMR (300 MHz, CDCl₃) δ(ppm): AB system (δ_(A)=8.01, δ_(B)=7.39,J_(AB)=8.5 Hz, 4H), 6.08-6.00 (m, 1H), 4.73 (d, J=6.3 Hz, 2H), 3.95 (s,6H), 3.92 (s, 3H).

[0497] The title compound 212 was obtained from 211 in 2 steps followingthe same procedure as Example 1, steps 4 and 5. ¹H NMR (300 MHz,acetone-d₆+ΣDMSO-d₆) δ(ppm): 9.58 (bs, 1H), 8.27 (t, J=6.3 Hz, 1H), ABsystem (δ_(A)=8.04, δ_(B)=7.53, J_(AB=)8.4 Hz, 4H), 7.31 (d, J=6.9 Hz,1H), ), 7.02 (td, J=7.6, 1.6 Hz, 1H), 6.88 (dd, J=7.9, 1.4 Hz, 1H), 6.68(td, J=7.6, 1.4 Hz, 1H), 4.86-4.78 (m, 2H), 4.69 (d, J=6.3 Hz, 2H), ),3.90 and 3.89 (2s, 6H). HRMS (calc.): 380.1597, (found): 380.1601.

[0498] Step 2:N-(2-Amino-phenyl)-4-[(4,6-dimethoxy-[1,3,5]-triazin-2-yl-amino)-methyl]-benzamide(212)

Example 139

[0499] Step 1:4-[(6-(2-Indanyl-amino)-4-methoxy-[1,3,5]triazin-2-yl-amino)-methyl]-benzoicacid (213)

[0500] To a stirred solution at room temperature of 5 (300 mg, 0.73mmol) in a mixture of MeOH/THF (10 ml/5 ml) was added an aqueoussolution of KOH (10%, 5 ml). After 3 days, the reaction mixture wasconcentrated on the rotavap, diluted in water and acidified with 1N HCluntil pH 5-6 in order to get a white precipitate. After 15 min, thesuspension was filtered off and the cake was abundantly washed withwater, and dried to afford the title compound 213 (282 mg, 0.72 mmol,98% yield) as a white solid. MS: m/z=392.1 [MH]⁺.

[0501] Step 2:N-(2-amino-phenyl)-4-{[6-(2-indanyl-amino)-4-methoxy-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide(214)

[0502] The title compound 214 was obtained from 213 in one stepfollowing the same procedure as Example 1, step 5. ¹H NMR (300 MHz,acetone-d₆+

DMSO-d₆) δ(ppm): mixture of rotamers, 9.69-9.53 (m, 1H), AB system(δ_(A)=8.04, δ_(B)=7.52, J_(AB)=7.8 Hz, 4H), 7.80-7.60 (m, 1H),7.45-7.10 (m, 6H), 7.01 (t, J=7.6 Hz, 1H), 6.88 (d, J=8.2 Hz, 1H), 6.68(t, J=7.6 Hz, 1H), 4.92-4.60 (m, 5H), 3.90-3.78 (m, 3H), 3.35-3.22 (m,2H), 3.02-2.83 (m, 2H). HRMS (calc.): 481.2226, (found): 481.2231.

Example 29

[0503] Step 1: Methyl4-[(4,6-dichloro-[1,3,5]triazin-2-yl-N-methyl-amino)-methyl]-benzoicester (216)

[0504] To a stirred suspension at room temperature of NaH (95%, 81 mg,3.19 mmol) in anhydrous THF (10 ml) under nitrogen were successivelyadded a solution of 3 (500 mg, 1.60 mmol) in anhydrous THF (10 ml) andMel (298 μl, 4.79 mmol). After 16 h, the reaction mixture was pouredinto a saturated aqueous solution of NH₄Cl, and diluted with AcOEt.After separation, the organic layer was successively washed with sat.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/hexane: 10/90→20/80) to afford thetitle compound 215 (200 mg, 0.61 mmol, 38% yield) as a white crystallinesolid. ¹H NMR (300 MHz, CDCl₃) δ(ppm): AB system (δ_(A)=8.04,δ_(B)=7.31, J_(AB)=8.2 Hz, 4H), 4.93 (s, 2H), 3.93 (s, 3H), 3.18 (s,3H).

[0505] Step 2:4-{[4-amino-6-(2-indanyl-amino)-[1,3,5]-triazin-2-yl-N-methyl-amino]-methyl}-N-(2-amino-phenyl)-benzamide(216)

[0506] The title compound 216 from 215 in 4 steps was obtained followingthe same procedure as Example 1, Pathway B steps 2-5. ¹H NMR (300 MHz,acetone-d₆) δ(ppm): 9.11 (bs, 1H), 8.03 (d, J=8.0 Hz, 2H), 7.43 (bs,2H), 7.33 (d, J=7.7 Hz, 1H), ), 7.28-7.09 (m, 4H), 7.04 (td, J=7.6, 1.5Hz, 1H), 6.90 (dd, J=8.0, 1.4 Hz, 1H), 6.71 (td, J=7.5, 1.3 Hz, 1H),6.25-6.05 (m, 1H), 5.82 and 5.64 (2bs, 2H), 5.00-4.56 (m, 5H), 3.42-2.76(m, 7H). HRMS (calc.): 480.2386. (found): 480.2377.

Example 141

[0507] Step 1: Methyl4-[(4-chloro-6-methyl-[1,3,5]triazin-2-yl-amino)-methyl]-benzoic ester(217)

[0508] To a stirred solution at −30° C. of cyanuric chloride 1 (2.00 g,10.85 mmol) in anhydrous THF (100 ml) under nitrogen was slowly added asolution of MeMgBr (17 ml, 23.86 mmol, 1.4 M in anhydrous THF/toluene).After 1 h, the reaction mixture was allowed to warm to room temperatureover 3 h. Then, methyl 4-(aminomethyl)benzoate.HCl 2 (2.08 g, 10.30mmol) and i-Pr₂NEt (3.78 ml, 21.69 mmol) were added, respectively. After18 h, the reaction mixture was poured into a saturated aqueous solutionof NH₄Cl, and diluted with AcOEt. After separation, the organic layerwas successively washed with sat. NH₄Cl, H₂O and brine, dried overanhydrous MgSO₄, filtered and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (AcOEt/CH₂Cl₂:10/90→15/85) to afford the title compound 217 (780 mg, 2.67 mmol, 25%yield) as a yellow powder. ¹H NMR (300 MHz, CDCl₃) δ(ppm): mixture ofrotamers, 2 AB system (δ_(A)=8.03, δ_(A′)=8.02, δ_(B)=7.39, δ_(B′)=7.38,J=8.5 Hz, 4H), 6.28-6.08 (2 m, 1H), 4.76 and 4.74 (2d, J=6.3 Hz, 2H),3.92 (s, 3H), 2.46 and 2.42 (2s, 3H).

[0509] Step 2:N-(2-amino-phenyl)-4-{[6-(2-indanyl-amino)-4-methyl-[1,3,5]-triazin-2-yl-amino]-methyl}-benzamide(218)

[0510] The title compound 218 was obtained from 217 in 3 steps followingthe same procedure as Example 1, steps 3-5. ¹H NMR (300 MHz,acetone-d₆+ΣDMSO-d₆) δ(ppm): mixture of rotamers, 9.62-9.50 (m, 1H),8.04 (d, J=8.0 Hz, 2H), 7.68-7.37 (m, 3H), 7.33 (d, J=7.7 Hz, 1H),7.28-7.07 (m, 5H), 7.02 (t, J=7.4 Hz, 1H), 6.89 (d, J=7.9 Hz, 1H), 6.69(t, J=7.4 Hz, 1H), 4.92-4.60 (m, 5H), 3.35-3.10 (m, 2H), 3.02-2.82 (m,2H), 2.25-2.12 (m, 3H).

Example 142

[0511] Step 1:(2-{4-[2-(4,6-Diamino-[1,3,5]triazin-2-yl)-vinyl]-benzoylamino}-phenyl)-carbamictert-butyl ester (219)

[0512] To a degazed solution of 184 (40 mg, 0.091 mmol) and2-vinyl-4,6-diamino-1,3,5-triazine (11 mg, 0.083 mmol) in dry DMF (1 mL)was added tri-o-tolylphosphine (POT) (1.5 mg, 0.005 mmol) followed byEt₃N (46 μL, 0.33 mmol) and tris(dibenzylideneacetone)dipalladium(0) (2mg, 0.0025 mmol). The solution was heated at 100° C. for 16h. Then, DMFwas removed under reduced pressure. The reaction mixture was partitionedbetween AcOEt and a solution of sat. NH₄Cl. After separation, theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was then purified by flashchromatography on silica gel (MeOH/CH₂Cl₂: 5/95) to afford the titlecompound 219 (25 mg, 0.056 mmol, 67% yield). ¹H NMR (300 MHz,Acetone-d₆) δ(ppm): 8.27 (s, 1H), 8.06 (d, J=8.1 Hz, 2H), 7.96 (d,J=15.9 Hz, 1H), 7.79 (d, J=8.1 Hz, 2H), 7.76-7.69 (m, 1H), 7.62-7.55 (m,1H), 7.26-7.15 (m, 2H), 6.90 (d, J=15.9 Hz), 6.21 (s, 4H), 1.50 (s, 9H).

[0513] Step 2:N-(2-Amino-phenyl)-4-[2-(4,6-diamino-[1,3,5]triazin-2-yl)-vinyl]-benzamide(220)

[0514] To a stirred solution at room temperature of 219 (25 mg, 0.056mmol) in CH₂Cl₂ (1.5 mL) was added TFA (0.3 mL, 4.3 mmol). After 30 min,a solution of sat. NaHCO₃ was slowly added until pH 8 is reached, CH₂Cl₂was removed under reduced pressure, AcOEt was added, and the phases wereseparated. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude residue was purified byflash chromatography on silica gel (MeOH/CH₂Cl₂: 10/90) to afford thetitle compound 220 (19 mg, 0.054 mmol, 98% yield). ¹H NMR (300 MHz,acetone-d₆) δ(ppm): 8.33, 8.13 (2d, J=7.5 Hz, 1H), 8.22 (d, J=15.9 Hz,1H), 8.01 (d, J=8.1 Hz, 2H), 7.84 (d, J=8.1 Hz, 2H), 7.38-6.96 (m, 2H),7.03 (d, J=15.9 Hz, 1H), 6.94-6.62 (m, 2H).

Example 143a

[0515] Step 1: 2-Amino-4-chloro-6-piperidin-1-yl-[1,3,5]triazin (221)

[0516] Ammonia was bubbled for 5 min in a solution of2,4-dichloro-6-piperidin-1-yl-[1,3,5]triazine (500 mg, 2.15 mmol) in dry1,4-dioxane (20 mL). The solution was heated at 70° C. for 16 h in asealed tube. The reaction mixture was allowed to cool to roomtemperature, and partitioned between AcOEt and a solution of sat. NH₄Cl.After separation, the organic layer was washed with water and brine,dried over anhydrous Na₂SO₄, filtered and concentrated to afford thetitle compound 221 (453 mg, 2.12 mmol, 98% yield). LRMS: [MH]⁺=214.1.

[0517] Step 2: 2-Amino 4-piperidin-1-yl-6-vinyl-[1,3,5]triazin (222)

[0518] To a solution of 221 (358 mg, 1.68 mmol) in dry toluene (7 mL)was added tributyl(vinyl)tin (514 μL, 1.76 mmol) followed by Pd(PPh₃)₄(97 mg, 0.084 mmol) and the reaction mixture was heated at 100° C. for16 h in a sealed tube. Then, the reaction mixture was allowed to cool toroom temperature, concentrated, and purified directly by flashchromatography on silica gel (AcOEt/hexane: 10/90→30/70) to afford thetitle compound 222 (containing tributyltin chloride).

[0519] Steps 3:N-(2-Amino-phenyl)-4-[2-(4-amino-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-vinyl]-benzamide223)

[0520] The title compound 223 was obtained from 222 in 2 steps followingthe same procedure as in scheme 31, steps 1 and 2. ¹H NMR: (300 MHz,DMSO-d₆) δ(ppm): 9.69 (s, 1H), 8.01 (d, J=7.5 Hz, 2H), 7.87 (d, J=16.0Hz, 1H), 7.80 (d, J=7.5 Hz, 2H), 7.18 (d, J=7.5 Hz, 1H), 7.04-6.92 (m,1H), 6.91 (d, J=16 Hz, 1H), 6.85-6.68 (m, 3H), 6.60 (t, J=7.2 Hz, 1H),4.93 (s, 2H), 3.77 (s, 4H), 1.63 (s, 2H), 1.52 (s, 4H).

Example 143b

[0521] Step 4:N-(2-Amino-phenyl)-4-[2-(4-amino-6-piperidin-1-yl-[1,3,5]triazin-2-yl)-ethyl]-benzamide(224)

[0522] To a solution of 223 (18 mg, 0.043 mmol) in MeOH (5 mL) was added10% Pd/C (10 mg, 0.021 mmol). The reaction mixture was shaked under apressure of H₂ (40 psi) at room temperature for 16 h using anhydrogenation apparatus. Then, the reaction mixture was purged with N₂,filtered through celite, and concentrated. The crude residue was thenpurified by flash chromatography on silica gel (MeOH/CH₂Cl₂: 2/98→4/96)to afford the title compound 224 (10 mg, 0.024 mmol, 56% yield). ¹H NMR(300 MHz, CDCl₃—CD₃OD) δ(ppm): 7.82 (d, J=8.1 Hz, 2H), 7.35 (d, J=8.1Hz, 2H), 7.08 (t, J=7.0 Hz, 1H), 6.89-6.79 (m, 2H), 7.80-6.90 (m, 1H),3.76 (s, 4H), 3.13 (t, J=8.1 Hz, 2H), 2.88 (t, J=8.1 Hz, 2H),1.90-1.40(m, 10H).

Example 144

[0523] Step 1: 2-Amino-benzothiazol-6-ol (225)

[0524] A suspension of 2-amino-6-methoxybenzothiazole (5.00 g, 27.8mmol) in dichloromethane (70 mL) was cooled to 0° C. under nitrogen andboron tribromide (3.93 mL, 41.6 mmol) was added dropwise. The lightyellow mixture was stirred for 3 h, allowing to warm-up slowly from 0°C. to 10° C. The reaction was slowly quenched by dropwise addition ofmethanol and tafter stirring overnight at room temperature, the whitesolid was collected by filtration (6.04 g, 88% yield). This hydrobromicsalt was dissolved in water, washed with ethyl acetate, and neutralizedwith a saturated aqueous solution of NaHCO₃. The resulting crystals werecollected by filtration and dried in the oven at 135° C. for 1 h toafford the title compound 225 as colorless crystals (3.63 g, 79% yield).¹H NMR: (CD₃OD) δ(ppm): 7.27 (d, J=8.8 Hz, 1H), 7.08 (d, J=2.2 Hz, 1H),6.80 (dd, J=8.4, 2.2 Hz, 1H).

[0525] Step 2: 6-(2-Morpholin-4-yl-ethoxy)-benzothiazol-2-ylamine (226)

[0526] To a solution of benzothiazole 225 (3.62 g, 21.8 mmol) in THF atroom temperature under nitrogen, were successively added4-(2-hydroxyethyl)morpholine (3.17 mL, 26.1 mmol), triphenylphosphine(7.43 g, 28.3 mmol) followed by a dropwise addition of diethylazodicarboxylate (4.46 mL, 28.3 mmol). The solution was stirred for 3.5h and THF was partially removed in vacuo. The mixture was partitionedbetween ethyl acetate and H₂O. The combined organic layers wereextracted with 1N HCl. The combined acidic extracts were neutralizedusing a saturated aqueous solution of NaHCO₃ and the precipitate wasdissolved with ethyl acetate. These combined organic layers were washedwith brine, dried over MgSO₄, and concentrated. The filtrate wasconcentrated to afford the title compound 226 (5.83 g, 96% yield) as alight yellow oil. ¹H NMR: (Acetone-d₆) δ(ppm): 7.37 (d, J=8.8 Hz, 1H),7.34 (d, J=2.6 Hz, 1H), 6.94 (dd, J=8.8, 2.6 Hz, 1H), 6.60 (bs, 2H),4.19 (t, J=6.2 Hz, 2H), 3.70-3.67 (m, 4H), 2.90 (s, 2H), 2.81 (t, J=6.2Hz, 2H), 2.62-2.58 (m, 4H).

[0527] Step 3:4-{[6-(2-Morpholin4-yl-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzoicacid methyl ester (227)

[0528] To a round-bottom flask containing benzothiazole 226 (5.80 g,20.8 mmol) was added methyl 4-formylbenzoate (5.11 g, 31.1 mmol),followed by THF (8 mL), dibutyltin dichloride (315 mg, 1.04 mmol) anddropwise addition of phenylsilane (3.24 mL, 31.1 mmol). The resultingmixture was stirred overnight at room temperature under nitrogen. Themixture was diluted in ethyl acetate and filtered. The filtrate waspartitioned between ethyl acetate and water and the combined organiclayers were washed with 1N HCl. The combined acidic layers wereneutralized using a saturated aqueous solution of NaHCO₃ and theprecipitate was extracted with ethyl aceate. The combined organic layerswere washed with brine, dried over MgSO₄, and concentrated. Theresulting crude was purified by flash chromatography using MeOH/CHCl₃(10:90) to afford 227 (3.69 g, 42% yield). ¹H NMR: (Acetone-d₆) δ(ppm):8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8 Hz, 1H),7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t, J=5.5 Hz,2H), 3.86 (s, 3H).

[0529] Step 4:N-(2-Amino-phenyl)-4-{[6-(2-morpholin-4-yl-ethoxy)-benzothiazol-2-ylamino]-methyl}-benzamide(228)

[0530] Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 228 wasobtained (958 mg, 46%) as a colorless solid. ¹H NMR: (CD₃OD) δ(ppm):8.04 (d, J=8.2 Hz, 2H), 7.62 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.8 Hz, 1H),7.31 (d, J=2.5 Hz, 1H), 7.25 (d, J=7.4 Hz, 1H), 7.15 (t, J=7.4 Hz, 1H),6.97 (dd, J=8.8, 2.5 Hz, 2H), 6.84 (t, J=7.4 Hz, 1H), 4.78 (s, 2H), 4.21(t, J=5.2 Hz, 2H), 3.81-3.77 (m, 4H), 2.87 (t, J=5.5. 2H), 2.69-3.66 (m,4H).

Example 145

[0531] Step 1: 4-[(5-Bromo-benzothiazol-2-ylamino)-methyl]-benzoic acidmethyl ester (229)

[0532] Following the procedure described in Example 144, step 3, butsubstituting the 2-amino-6-bromobenzothiazole for 226, the titlecompound 229 was obtained in 56% yield. ¹H NMR: (DMSO-d₆) δ(ppm): 8.78(t, J=5.9 Hz, 1H), 8.01 (d, J=8.2 Hz, 2H), 7.99 (s, 1H), 7.56 (d, J=8.2Hz, 2H), 7.43-7.34 (m, 2H), 4.74 (d, J=5.9 Hz, 2H), 3.90 (s, 3H).

[0533] Step 2:4-{[5-(3,4,5-Trimethoxy-phenyl)-benzothiazol-2-ylamino]-methyl}-benzoicacid methyl ester (230)

[0534] Following the procedure described in Example 15, step 1, butsubstituting 229 for 140, the title compound 230 was obtained in44%yield as colorless crystals. ¹H NMR: (DMSO-d₆) δ(ppm): 8.73 (t, J=5.7Hz, 1H), 8.11 (d, J=1.8 Hz, 1H), 8.02 (d, J=8.4 Hz, 2H), 7.63-7.57 (m,3H), 7.48 (d, J=8.4 Hz, 1H), 6.97 (s, 2H), 4.77 (d, J=5.7 Hz, 2H), 3.92(m, 6H), 3.90 (s, 3H), 3.74 (s, 3H).

[0535] Step 3:N-(2-Amino-phenyl)-4-{[5-(3,4,5-trimethoxy-phenyl)-benzothiazol-2-ylamino]-methyl}-benzamide(231)

[0536] Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 231 wasobtained in 69% yield. ¹H NMR: (Acetone-d₆) δ(ppm): 8.31 (d, J=7.9 Hz,2H), 8.20 (d, J=7.5 Hz, 1H), 8.13 (s, 1H), 7.73-7.58 (m, 3H), 7.63 (d,J=7.5 Hz, 2H), 7.48-7.43 (m, 2H), 7.05 (s, 2H), 4.98 (s, 2H), 4.00 (s,6H), 3.84 (s, 3H).

Example 146

[0537] Step 1: 4-[(6-Methoxy-benzothiazol-2-ylamino)-methyl]-benzoicacid methyl ester (232)

[0538] To a solution of 2-amino-6-methoxybenzothiazole (2.00 g, 11.1mmol) in a mixture of dichloroethane (20 mL) and THF (20 mL), weresuccessively added methyl 4-formylbenzoate (1.82 g, 11.1 mmol), sodiumtriacetoxyborohydride (3.53 g, 16.7 mmol) and acetic acid (1.27 mL, 22.2mmol). The mixture was stirred over 2 days and was quenched by addingaqueous saturated solution of NaHCO₃. The mixture was poured in aseparating funnel containing water and was extracted withdichloromethane. The combined organic extracts were washed with brine,dried over MgSO₄ and concentrated in vacuo. The crude material waspurified by flash chromatography using EtOAc/hexane (20:80 to 30:70) toafford the title compound 232 (1.85 g, 51% yield). ¹H NMR: (Acetone-d₆)δ(ppm): 8.04 (d, J=8.5 Hz, 2H), 7.65 (d, J=8.8 Hz, 2H), 7.41 (d, J=8.8Hz, 1H), 7.34 (d, J=2.5 Hz, 1H), 6.94 (dd, J=8.5, 2.7 Hz, 1H), 4.50 (t,J=5.5 Hz, 2H), 3.86 (s, 3H).

[0539] Step 2:N-(2-Amino-phenyl)-4-[(6-methoxy-benzothiazol-2-ylamino)-methyl]-benzamide(233)

[0540] Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 233 wasobtained in 19% yield as a light beige solid. ¹H NMR: (DMSO-d₆) δ(ppm):9.68 (s, 1H), 8.44 (t, J=5.8 Hz, 1H), 8.00 (d, J=8.2 Hz, 2H), 7.55 (d,J=8.2 Hz, 2H), 7.39 (d, J=2.7 Hz, 1H), 7.34 (d, J=8.8 Hz, 1H), 7.21 (d,J=6.6 Hz, 1H), 7.05 (t, J=6.3 Hz, 1H), 7.00 (d, J=1.4 Hz, 1H), 6.88 (dd,J=8.8, 2.7 Hz, 1H), 6.86 (dd, J=8.0, 1.4 Hz, 1H), 6.65 (td, J=7.4, 1.4Hz, 1H), 4.95 (s, 2H), 4.70 (d, J=5.8 Hz, 2H), 3.79 (s, 3H).

Example 147

[0541] Step 1: 4-(6-Methoxy-1H-benzoimidazol-2-ylsulfanylmethyl)-benzoicacid methyl ester hydrobromide (234)

[0542] To a solution of methyl 4-(bromomethyl)benzoate (2.51 g, 11.0mmol) in DMF (50 mL) was added 5-methoxy-2-benzimidazolethiol (1.98 g,11.0 mmol). The mixture was stirred at room temperature for 24 h and thesolvent was evaporated in vacuo. The residue was suspended in ethylacetate and the hydrobromide salt was collected by filtration to affordthe title compound 234 (4.10 g, 91% yield) as a colorless solid. ¹H NMR:(DMSO-d₆) δ(ppm): 7.90 (d, J=8.2 Hz, 2H), 7.55 (d, J=8.2 Hz, 2H), 7.45(d, J=8.2 Hz, 1H), 7.03 (s,1H), 6.94 (d, J=8.2 Hz,1H), 4.65 (s,2H), 3.82(s,3H), 3.79 (s, 3H).

[0543] Step 2:4-[6-(2-Morpholin4-yl-ethoxy)-1H-benzoimidazol-2-ylsulfanylmethyl]-benzoicacid methyl ester (235)

[0544] Following the procedure described in Example 144, step 1, 2 butsubstituting the previous compound for 2-amino-6-methoxybenzothiazole,the title compound 235 was obtained in 37% yield. ¹H NMR: (CDCl₃)δ(ppm): 8.04-8.00 (m, 2H), 7.77-7.72 (m, 1H), 7.69-7.59 (m, 1H),7.56-7.49 (m, 2H), 6.96-6.90 (m, 1H), 4.68 (s, 2H), 4.31-4.16 (m, 4H),3.97 (s, 3H), 3.98-3.91 (m, 2H), 3.82-3.72 (m, 2H), 2.75-2.47 (m, 4H).

[0545] Step 3:N-(2-Amino-phenyl)-4-[6-(2-morpholin-4-yl-ethoxy)-1H-benzoimidazol-2-ylsulfanylmethyl]-benzamide(236)

[0546] Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 236 wasobtained in 11% yield. ¹H NMR: (CD₃OD) δ(ppm): 7.89 (d, J=8.2 Hz, 2H),7.45 (d, J=8.2 Hz, 2H), 7.28 (d, J=8.5 Hz, 1H), 7.19-7.06 (m, 3H),6.93-6.79 (m, 3H), 4.55 (s, 2H), 4.18 (t, J=6.3 Hz, 2H), 3.65-3.62 (m,4H), 2.51 (t, J=6.6 Hz, 2H), 2.46-2.42 (m, 4H).

Example 148

[0547] Step 1: 4-Morpholin-4-yl-benzoic acid methyl ester (237)

[0548] A flame-dried pressure vessel was charged with cesium carbonate(912 mg, 2.80 mmol) and toluene (8 mL) and the flasked was purged withnitrogen. Palladium acetate (9.0 mg, 0.004 mmol) andrac-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (37 mg, 0.06 mmol). Themixture was degassed and heated at 100° C. for 18 h. It was allowed tocool to room temperature and was filtered through celite, rinsed withethyl acetate and partitioned between ethyl acetate and water. Theorganic layer was washed with a saturated solution of NaHCO₃, brine,dried over MgSO₄ and concentrated in vacuo to afford the title compound237 (443 mg, 100% yield). ¹H NMR: (CDCl₃) δ(ppm):8.02 (d, J=9.2 Hz, 2H),6.95 (d, J=8.8 Hz, 2H), 3.95 (s, 4H), 3.92 (s, 3H), 3.38-3.35 (m, 4H).

[0549] Step 2: N-(2-Amino-phenyl)-4-morpholin-4-yl-benzamide (238)

[0550] Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 238 wasobtained in 33% yield. ¹H NMR: (DMSO-d₆) δ(ppm): 7.20 (d, J=7.9 Hz, 1H),7.07 (d, J=8.8 Hz, 2H), 7.01 (t, J=7.0 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H),6.65 (t, J=7.5 Hz, 1H), 4.90 (s, 2H), 3.81-3.79 (m, 4H), 3.32-3.28 (m,4H).

Example 149

[0551] Step 1: 3-Methylsulfanyl-3-(pyridin-4-ylamino)-acrylonitrile(239)

[0552] To a solution of pyridin-4-ylamine (1.0 g, 11.0 mmol) and3,3-Bis-methylsulfanyl-acrylonitrile (2.05 g, 12.6 mmol) in DMF at roomtemperature, was added powdered 4A molecular sieves. The mixture wasstirred for 1 hr. Subsequently the mixture was cooled to 0° C., 60% NaHdispersion in oil (0.92 g, 23.0 mmol) was added portionwise over 1 hr.and it was stirred at 0° C. for an additional 2 hrs. The cold bath wasremoved and the mixture was stirred at room temperature for 20 hrs. DMFwas removed in vacuo and the crude was purified by column chromatography(gradient of EtOAc to 25% MeOH/EtOAc) to afford the desired product asan off-white solid (1.9 g, 89%).

[0553] Step 2:N-(2-Amino-phenyl)-4-{[2-cyano-1-(pyridin-4-ylamino)-vinylamino]-methyl}-benzamide(240)

[0554] To a mixture of3-methylsulfanyl-3-(pyridin-4-ylamino)-acrylonitrile (0.2 g, 1.0 mmol),4-aminomethyl-benzoic acid (0.173 g, 1.14 mmol), DMAP (1 mg) and Et₃N(0.14 ml, 1.0 mmol) was added dry pyridine (0.5 ml). The resultingstirring mixture was heated to 55° C. for 4.5 hrs., additional Et₃N(0.14 ml) was added and mixture was heated from 75° C. to 90° C. over aperiod of ˜30 hrs. When the reaction was complete, pyridine waspartially removed in vacuo and the crude was purified by columnchromatography (gradient of EtOAc to 20% MeOH/EtOAc) to afford thedesired product as an off-white solid (130 mg, 44%).

[0555] Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 240 wasobtained in 33% yield. ¹H NMR: ¹H NMR: (300 MHz, DMSO-d₆) δ(ppm): 9.69(br, 2H), 8.48 (br, 3H), 8.03 (d, J=7.9 Hz, 2H), 7.51 (d, J=8.4 Hz, 2H),7.29 (br, 2H), 7.23 (d, J=7.9 Hz, 1H), 7.03 (t, J=7.0 Hz, 1H), 6.84 (d,J=7.9 Hz, 1H), 6.65 (t, J=7.3 Hz, 1H), 4.96 (br, 2H), 4.62 (d, J=5.7 Hz,2H).

Example 150

[0556] Step 1: 4-[(2-Chloro-9H-purin-6-ylamino)-methyl]-benzoic acidmethyl ester (241)

[0557] A suspension of 2,6-dichloro-9H-purine (1 g, 5.29 mmol),4-aminomethyl-benzoic acid methyl ester hydrochloride (1.2 equiv., 1.28g) and NaHCO₃ (2.1 equiv., 935 mg) in water was heated at 100° C. Thehomogeneous solution thus formed was refluxed 30 min. The resultingwhite precipitate was filtered, washed with cold water and dried undervacuum giving the title compound 241 (1 g, 3.14 mmol, 60%). LRMScalc:317.7, found: 318.3 (MH)⁺.

[0558] Step 2:4-{[2-Chloro-9-(2-methoxy-ethyl)-9H-purin-6-ylamino]-methyl}-benzoicacid methyl ester (242)

[0559] Following the procedure described in Example 144, step 2 butsubstituting the previous compound for 2-amino-6-methoxybenzothiazole,the title compound 242 was obtained in 41% yield.

[0560] Step 3:N-(2-Amino-phenyl)-4-{[2-chloro-9-(2-methoxy-ethyl)-9H-purin-6-ylamino]-methyl}-benzamide(243)

[0561] Following the procedure described in Example 1, step 4, 5 butsubstituting the previous compound for 6, the title compound 243 wasobtained in 85% yield. ¹H NMR (CDCl₃) δ(ppm): 9.64 (s, 1H), 8.94 (bs,1H), 8.18 (s, 1H), 7.96 (d, J=7.8 Hz, 2H), 7.52 (d, J=7.8 Hz, 2H), 7.21(d. J=7.7 Hz, 1H), 7,01 (dd, J=7.3, 8.0 Hz, 1H), 6.81 (d, J=8.0 Hz, 1H),6.62 (dd, J=7.3, 7.7 Hz, 1H), 4.91 (bs, 2H), 4.78 (bs, 2H), 4.18 (m,2H), 3.70 (m, 2H), 3.26 (s, 3H)

Example 151

[0562] Step 1:Methyl-4-{[3-(2-chloro-6-fluoro-phenyl)-5-methyl-isoxazole-4-carbonyl]-amino-methyl}-benzoicacid ester (244)

[0563] To a stirred suspension at 0° C. of methyl4-(aminomethyl)benzoate.HCl 2 (809 mg, 4.01 mmol) in anhydrous CH₂Cl₂(25 ml) under nitrogen were successively added i-Pr₂NEt (1.91 ml, 10.95mmol) and 3-(2-chloro-6-fluorophenyl)-5-methylisoxazole-4-carbonylchloride (1.00 g, 3.65 mmol). After 45 min, the reaction mixture wasallowed to warm up to room temperature for 3 h. Then, the reactionmixture was concentrated, diluted with AcOEt, and successively washedwith sat. NH₄Cl, H₂O, sat. NaHCO₃, H₂O and brine, dried over anhydrousMgSO₄, filtered and concentrated to afford the title compound 244 (1.50g, quantitative yield) as a colorless sticky foam. ¹H NMR (300 MHz,CDCl₃) δ(ppm): 7.93 (d, J=7.9 Hz, 2H), 7.46-7.35 (m, 1H), 7.29 (d, J=8.4Hz, 1H), 7.15-7.05 (m, 3H), 5.49 (bs, 1H), 4.46 (d, J=5.7 Hz, 2H), 3.92(s, 3H), 2.80 (s, 3H).

[0564] Step 2:4-{[3-(2-Chloro-6-fluoro-phenyl)-5-methyl-isoxazole4-carbonyl]-amino-methyl}-benzoicacid (245)

[0565] To a stirred solution at room temperature of 244 (1.45 g, 3.60mmol) in THF (20 ml) was added a solution of LiOH.H₂O (453 mg, 10.80mmol) in water (20 ml). After 20 h, the reaction mixture wasconcentrated, diluted with water and acidified with 1N HCl until pH 6 inorder to get a white precipitate. After 10 min, the suspension wasfiltered off and the cake was abundantly washed with water, and dried toafford the title compound 245 (1.23 g, 3.15 mmol, 88% yield) as a whitesolid. ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 8.69 (t, J=5.9 Hz, 1H), 7.91(d, J=7.9 Hz, 2H), 7.70-7.58 (m, 1H), 7.51 (d, J=7.9 Hz, 1H), 7.45-7.30(m, 3H), 4.44 (d, J=5.7 Hz, 2H), 2.72 (s, 3H).

[0566] Step 3:4-(9-Chloro-3-methyl-4-oxo-4H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-benzoicacid (246)

[0567] To a stirred suspension at room temperature of 245 (795 mg, 2.05mmol) in anhydrous DMF (10 ml) was added a solution of NaOH (409 mg,10.22 mmol) in anhydrous MeOH (5.1 ml). Then, the reaction mixture waswarmed up to 40° C. After 3 days, the reaction mixture was concentrated,diluted with water and acidified with 1N HCl until pH 5 in order to geta pale pinky precipitate. After 30 min, the suspension was filtered offand the cake was abundantly washed with water, and dried to afford thetitle compound 246 (679 mg, 1.84 mmol, 90% yield) as a pale pinky solid.¹H NMR (300 MHz, DMSO-d₆) δ(ppm): AB system (δ_(A)=7.92, δ_(B)=7.40,J=8.4 Hz, 4H), 7.56 (t, J=8.1 Hz, 1H), 7.47 (d, J=7.5 Hz, 1H), 7.31 (d,J=8.3 Hz, 1H), 5.59 (bs, 2H), 2.95 (s, 3H).

[0568] Step 4:N-(2-Amino-phenyl)-4-(9-chloro-3-methyl4-oxo-4H-isoxazolo[4,3-c]quinolin-5-ylmethyl)-benzamide(247)

[0569] The title compound 247 was obtained from 246 in one stepfollowing the same procedure as Example 1, steps 5. ¹H NMR (300 MHz,DMSO-d₆) δ(ppm): 9.65 (s, 1H), AB system (δ_(A)=7.95, δ_(B)=7.42, J=8.1Hz, 4H), 7.58 (t, J=8.1 Hz, 1H), 7.48 (d, J=7.5 Hz, 1H), 7.35 (d, J=8.3Hz, 1H), 7.17 (d, J=7.5 Hz, 1H), 7.00 (t, J=7.3 Hz, 1H), 6.80 (d, J=7.5Hz, 1H), 6.62 (t, J=7.3 Hz, 1H), 5.61 (bs, 2H), 4.91 (s, 2H), 2.97 (s,3H).

Example 152

[0570] Step 1: 4-(1H-Imidazol-2-yl-(benzoic acid (248)

[0571] To a stirred solution of 4-formylbenzoic acid (2.00 g, 12.3 mmol)in ammonium hydroxide (9 ml) was added glyoxal (2.86 ml, 20.0 mmol). Thereaction mixture was stirred 16 h at room temperature. 1N HCl was addedto the reaction mixture to acidify to pH 5. The solvent was evaporatedand the residue was triturated 30 min. in water (20 ml) and filtered toobtain the title compound 248 (2.08 g, 83%) as a white solid. LRMS:188.1 (Calc.); 189.1 (found).

[0572] Step 2: N-(2-Amino-phenyl)-4-(1H-imidazol-2-yl)-benzamide (249)

[0573] The title compound 249 was obtained following the same procedureas Example 1, step 5. ¹H NMR (CDCl₃) δ(ppm): ¹H NMR: (DMSO) δ(ppm): 9.72(bs, 1H), 8.07 (s, 4H), 7.26 (s, 2H), 7.18 (d, J=7.9 Hz, 1H), 6.98 (dd,J=7.5, 7.5 Hz, 1H), 6.79 (d, J=7.9 Hz, 1H), 6.60 (dd, J=7.5, 7.5 Hz,1H). MS: (calc.) 278.1; (obt.) 279.1 (MH)⁺.

Example 153

[0574] Step 1: 4-Thiocarbamoylmethyl-benzoic acid (250)

[0575] To a stirred suspension of 4-cyanomethyl-benzoic acid (1.65 g,10.24 mmol) and Et₃N (5 ml) in pyridine, H₂S was bubbled during 3 h. Thereaction mixture was stirred 16 h at room temperature. Water was thenadded to the reaction mixture which was agitated for 1 h beforeacidifying to pH 6 with 1M HCl. The solvent was evaporated and theresidue was triturated 30 min. in water (20 ml) and filtered to obtainthe title compound 250 (2.08 g, 83%) as a white solid. ¹H NMR (DMSO)δ(ppm): 12.85 (bs, 1H), 9.53 (bs, 1H), 9.43 (bs, 1H), 7.88 (d, J=8.1 Hz,2H), 7.44 (d. J=8.1 Hz, 2H), 3.88 (s, 2H).

[0576] Step 2: 4-(4-Chloromethyl-thiazol-2-ylmethyl)-benzoic acid (251)

[0577] A solution of 250 (729 mg, 3.73 mmol) and 1,3-dichloroacetone(474 mg, 3.73 mmol) in THF (30 ml) was stirred at 40° C. during 48 h.The solvent was evaporated then the residue was dissolved in ethylacetate, washed with brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was purified by flash chromatography onsilica gel (2-4% MeOH/CH₂Cl₂) to afford the title compound (827 mg, 83%yield) as a white solid. ¹H NMR (DMSO) δ(ppm): 12.93 (bs, 1H), 7.91 (d,J=8.1 Hz, 2H), 7.63 (s, 1H), 7.46 (d, J=8.1 Hz, 2H), 4.78 (s, 2H), 4.42(s, 2H).

[0578] Step 3:N-(2-Amino-phenyl)-4-(4-morpholin-4-ylmethyl-thiazol-2-ylmethyl)-benzamide(252)

[0579] K₂CO₃ (599 mg, 4.33 mmol) was added to a solution of 251 (527 mg,1.97 mmol) an morpholine (189

l, 2.17 mmol) in THF (15 ml) was refluxed during 48 h. The solvent wasevaporated. The crude residue was purified by flash chromatography onsilica gel (3-50% MeOH/CH₂Cl₂) to afford the title compound 252 (238 mg,38% yield) as a pale yellow solid. LRMS: 318.2 (calc) 319.2 (found).

[0580] The title compound 252 was obtained following the same procedureas Example 1, step 5. ¹H NMR (DMSO) δ(ppm): 9.63 (bs, 1H), 7.94 (d,J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H), 7.33 (s, 1H), 7.15 (d, J=8.1 Hz,1H), 6.97 (dd, J=7.7, 7.7 Hz, 1H), 6.77 (d, J=7.3 Hz, 1H), 6.59 (dd,J=8.1, 8.1 Hz, 1H), 4.90 (bs, 2H), 4.40 (s, 2H), 3.59-3.56 (m, 6H),2.44-2.38 (m, 4H). LMRS: 408.2 (calc) 409.2 (found).

Example 154

[0581] Step 1: Methyl3-[3-(4-methoxycarbonyl-benzyl)-ureido]-thiophene-2-carboxylate (253)

[0582] The procedure described by Nakao (K. Nakao, R. Shimizu, H.Kubota, M. Yasuhara, Y. Hashimura, T. Suzuki, T. Fujita and H. Ohmizu;Bioorg. Med. Chem. 1998, 6, 849-868.) was followed to afford the titlecompound 253 (1.01 g, 91%) as a yellow solid. ¹H NMR (CDCl₃) δ(ppm):9.55 (bs, 1H), 8.00-7.97 (m, 3H), 7.42-7.37 (m, 3H), 5.45 (t, J=5.8 Hz,1H), 4.52 (d, J=6.0 Hz, 2H), 3.91 (s, 3H), 3.82 (s, 3H).

[0583] Step 2:4-(2,4-Dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl)benzoicacid (254)

[0584] To a suspension of 253 (422 mg, 1.21 mmol) in MeOH (15 ml) wasadded NaOH (145 mg, 3.63 mmol). The reaction mixture was heated at 60°C. during 16 h. Water (1 ml) was then added and the reaction mixture wasstirred for 1 more hour. The solvent was evaporated and the residue wasdissolved in water and acidified to pH 5 with HCl 1M. The precipitatewas filtered to afford the desired compound 254 (348 mg, 95%) as a whitesolid. LRMS: 302.0 (Calc.); 303.0 (found).

[0585] Steps 3:N-(2-Amino-phenyl)-4-(1-ethyl-2,4-dioxo-1,4-dihydro-2H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzamide(255)

[0586] The title compound 255 was obtained as a yellow solid (73%)following the same procedure as Example 99, step 2, 3, then followed byExample 1, step 5. ¹H NMR: (DMSO) δ(ppm): 9.61 (bs, 1H, NH), 8.22 (d,J=5.5 Hz, 1H, CH), 7.91 (d, J=8.2 Hz, 2H, CH), 7.43-7.40 (m, 3H, CH),7.15 (d, J=7.4 Hz, 1H, CH), 6.96 (dd, J=7.6, 7.6 Hz, 1H, CH), 6.77 (d,J=7.1 Hz, 1H, CH), 6.59 (dd, J=7.4, 7.4 Hz, 1H, CH), 5.17 (s, 2H, NCH₂),4.88 (bs, 2H, NH₂) 4.09 (q, J=7.0, 2H, CH₂), 1.22 (t, J=7.0, 3H, CH₃).LRMS: 420.1 (calc.); 421.0 (found).

Example 155

[0587] Step 1: 3H-Thieno[3,2-d]pyrimidin-4-one (256)

[0588] Methyl-3-amino-2-thiophene carboxylate (510 mg, 3.24 mmol) wasdissolved in formamide (20 ml) and heated at 170° C. 16 h. The solventwas evaporated. The crude residue was then purified by flashchromatography on silica gel (2-4% MeOH/CH₂Cl₂) to afford the titlecompound 256 (157 mg, 32% yield). LRMS: 152.0 (Calc.); 152.9 (found).

[0589] Step 2:N-(2-Aminophenyl)-4-(4-oxo-4H-thieno[3,2-d]pyrimidin-3-ylmethyl)-benzamide(257)

[0590] Following the procedure described in Example 85, step 1 butsubstituting the previous compound for 119, followed by Example 1, step4, 5, the title compound 257 was obtained in 41% yield. ¹H NMR: (DMSO)δ(ppm): 9.61 (bs, 1H), 8.70 (s, 1H), 8.22 (dd, J=5.2, 0.5 Hz, 1H), 7.95(d, J=8.2 Hz, 2H), 7.47 (d, J=8.5 Hz, 2H), 7.44 (dd, J=5.2, 0.6 Hz, 1H),7.15 (d, J=7.7 Hz, 1H), 6.96 (dd, J=6.9, 6.9 Hz, 1H), 6.77 (d, J=7.1Hz,1H), 6.58 (dd, J=7.0, 7.0 Hz, 1H), 5.31 (s, 2H), 4.87 (bs, 2H). MS:376.1 (calc.); 377.1 (found).

Example 156

[0591] Step 1: Methyl 2-amino4,5-dimethyl-thiophene-3-carboxylate (258)

[0592] The procedure described by Hozien (Z. A. Hozien, F. M. Atta, Kh.M. Hassan, A. A. Abdel-Wahab and S. A. Ahmed; Synht. Commun.. 1996,26(20), 3733-3755.) was followed to afford the title compound 258 (1.44g, 17%) as a yellow solid. LRMS: 197.1 (Calc.); 200.1 (found).

[0593] Steps 2:N-(2-Amino-phenyl)-4-(5,6-dimethyl-4-oxo-4H-thieno[2,3-d]pyrimidin-3-ylmethyl)-benzamide(259)

[0594] Following the procedure described in Example 155, step 1, 2 butsubstituting 258 for 256, the title compound 259 was obtained as a whitesolid (55%). ¹H NMR: (DMSO) δ(ppm): 9.61 (bs, 1H), 8.57 (s, 1H), 7.94(d, J=8.0 Hz, 2H), 7.45 (d, J=7.7 Hz, 2H), 7.16 (d, J=7.7 Hz, 1H), 6.96(dd, J=7.6, 7.6 Hz, 1H), 6.77 (d, J=8.0 Hz, 1H), 6.59 (dd, J=7.4, 7.4Hz, 1H), 5.25 (s, 2H), 4.87 (bs, 2H), 2.39 (s, 3H), 2.37 (s, 3H). LRMS:404.1 (calc); 405.0 (found).

Example 157

[0595] Step 1: Methyl 4-(4-oxo-chroman-3-ylidenemethyl)-benzoate (260)

[0596] Concentrated H₂SO₄ (2 ml) was slowly added to a solution of4-chromanone (2.00 g, 13.50 mmol) and methyl4-formylbenzoate (2.11 g,12.86 mmol) in glacial acetic acid. The reaction mixture was stirred 16h at room temperature. The solvent was concentrated to half volume theresulting precipitate was filtered and rinsed with ethyl acetate toafford the title compound 260 (3.11 g, 82%) as a purple solid. ¹H NMR:(DMSO) δ(ppm): 8.05 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.6 Hz,. 1H), 7.79 (s,1H), 7.64-7.59(m, 3H), 7.15 (dd, J=7.6, 7.6 Hz, 1H), 7.07 (d, J=8.2 Hz,1H), 5.43 (s, 2H), 3.89 (s, 3H).

[0597] Step 2: Methyl-4-(4-oxo-4H-chromen-3-ylmethyl)-benzoate (261)

[0598] Water (0.2 ml) and RhCl₃.H₂O (7 mg, 0.034 mmol) was added to asuspension of compound 260 (200 mg, 0.680 mmol) in EtOH (2 ml) and CDCl₃(2 ml). The reaction mixture was stirred 16 h at 70° C. The reactionmixture was cooled down and diluted in ethyl acetate, washed with brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (0.5-1%MeOH/CH₂Cl₂)to afford the title compound 261 (118 mg, 59%) as a whitesolid. ¹H NMR: (DMSO) δ0 (ppm): 8.45 (s, 1H), 8.03 (dd, J=7.9, 1.8 Hz,1H), 7.87 (d, J=8.4 Hz, 2H), 7.83-7.77(m, 1H), 7.65 (d, J=8.3 Hz, 1H),7.50-7.43 (m3, 1H), 3.82 (s, 3H), 3.80 (s, 2H).

[0599] Step 3:N-(2-Amino-phenyl)-4-(4-oxo-4H-chromen-3-ylmethyl)-benzamide (262)

[0600] The title compound 262 was obtained following the same procedureas Example 1, step 4, 5. ¹H NMR: (DMSO) δ(ppm): 9.56 (bs, 1H), 8.45 (s,1H), 8.04 (d, J=7.9 Hz, 1H), 7.88 (d, J=8.4 Hz, 2H), 7.80 (dd, J=7.5,7.5 Hz, 1H), 7.65 (d, J=8.4 Hz, 1H), 7.51-7.42 (m, 3H), 7.14 (d, J=7.9Hz, 1H), 6.96 (dd, J=7.3, 7.3 Hz, 1H), 6.76 (d, J=7.9 Hz, 1H), 6.58 (dd,J=7.3, 7.3 Hz, 1H), 4.86 (bs, 2H), 3.80 (s, 2H). LRMS: 370.1 (calc.);371.1 (found).

Example 158

[0601] Step 2: Methyl 4-chroman-3-ylmethyl-benzoate (263)

[0602] Pd/C 10% was added to a suspension of 260 (200 mg, 0.68 mmol) inMeOH (40 ml) and DMA (10 ml) which was previously purged under vacuum.The reaction mixture was stirred during 4 h at room temperature. Afterevaporation of the MeOH, water was added to the oily residue and theprecipitate obtained was filtered. The crude residue was then purifiedby flash chromatography on silica gel (5-8% AcOEt/Hex )to afford thetitle compound 263 (114 mg, 59%) as a white solid. LRMS: 282.1 (Calc.);283.0 (found).

[0603] Step 3: N-(2-Amino-phenyl)-4-chroman-3-ylmethyl-benzamide (265)

[0604] The title compound 265 was obtained following the same procedureas Example 1, steps 4 and 5. ¹H NMR: (acetone) δ(ppm): 9.06 (bs, 1H),8.01 (d, J=7.9 Hz, 2H), 7.42 (d, J=8.4 Hz, 2H), 7.31 (d, J=7.9 Hz, 1H),7.08-6.98 (m, 3H), 6.87 (d, J=7.5 Hz, 1H),6.82-6.66 (m, 3H), 4.62 (s,2H), 4.22-4.17 (m, 1H), 4.88-3.81 (m, 1H), 2.88-2.71 (m, 3H), 2.61-2.53(m, 1H), 2.41-2.53 (m, 1H). LRMS: 358.2 (calc.); 359.1 (found).

Example 159

[0605] Step 2: Methyl 4-(4-oxo-chroman-3-ylmethyl)-benzoate (264)

[0606] A suspension of 260 (400 mg, 1.36 mmol) and benzenesulfonylhydrazine (702 mg, 4.08 mmol) in DMF (7 ml) was stirred at 100° C.during 48 h. The solvent was evaporated and the residue was diluted inAcOEt, washed with NH₄Cl sat., brine, dried over anhydrous MgSO₄,filtered and concentrated. The crude residue was then purified by flashchromatography on silica gel (5% AcOEt/HEx )to afford the title compound264 (170 mg, 42%) as a white solid. LRMS: 296.1 (Calc.); 297.0 (found).

[0607] Step 3: N-(2-Amino-phenyl)-4-(4-oxo-chroman-3-ylmethyl)-benzamide(266)

[0608] The title compound 266 was obtained following the same procedureas Example 1, steps 4 and 5. ¹H NMR: (acetone) δ(ppm): 9.62 (bs, 1H),7.93 (d, J=7.9 Hz, 2H), 7.79 (d, J=7.9 Hz, 1H), 7.58 (dd, J=7.0, 7.0 Hz,1H), 7.39 (d, J=7.9 Hz, 2H), 7.17-7.04 (m, 3H), 6.97 (dd, J=7.0, 7.0 Hz,1H), 6.78 (d, J=7.9 Hz, 1H), 6.60 (dd, J=7.5, 7.5 Hz, 1H), 4.88 (s, 2H),4.44-4.39 (m, 1H), 4.28-4.21 (m, 1H), 2.26-3.21 (m, 2H), 2.83-2.74 (m,1H). LRMS: 372.1 (cacl.); 372.1 (found).

Example 160

[0609] Step 1: Methyl4(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzoate (266)

[0610] Et₃N (3.18 ml, 22.8 mmol) was added to a stirring solution of2-H-1,4-benzoxazin-3-(4H)one (2.50 g, 16.8 mmol) and methyl4-formylbenzoate (4.59 g, 27.5 mmol) in Ac₂O (20 ml). The reactionmixture was refluxed 16 h. After this mixture was cooled for 3 days, thesolid was filtered and rinsed with ethyl acetate to afford the titlecompound 266 (657 mg, 13%) as a yellow solid. LRMS: 295.1 (Calc.); 296.0(found).

[0611] Step 2: Methyl4-(3-oxo-3,4-dihydro-benzo[1,4]oxazin-2-ylidenemethyl)-benzoate (267)

[0612] The title compound 267 was obtained following the same procedureas Example 158, step 2. LRMS: 297.1 (Calc.); 298.1 (found).

[0613] Step 3:N-(2-Amino-phenyl)-4-(4-ethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzamide(269)

[0614] The title compound 269 was obtained from 267 following the sameprocedure as Example 99, step 2, 3, then followed by Example 1, step 4,5. ¹H NMR: (DMSO) δ(ppm): 9.61 (bs, 1H), 7.91 (d, J=7.9 Hz, 2H), 7.39(d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.17 (d, J=7.5 Hz, 1H),7.11-6.91 (m, 4H), 6.77 (d, J=7.0 Hz, 1H), 6.60 (dd, J=7.0, 7.0 Hz, 1H),4.95-4.91 (m, 1H), 4.89 (bs, 2H), 3.95 (q, J=7.0 Hz, 2H), 3.28-3.22 (m,1H), 3.17-2.89 (m, 1H), 1.16 (t, J=7.0 Hz, 3H). LRMS: 401.2 (calc.);402.1 (obt.).

Example 161

[0615] Step 1:N-(2-Amino-phenyl)-4-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-2-ylmethyl)-benzamide(270)

[0616] The title compound 270 was obtained from 267 following the sameprocedure as Example 1, step 4, 5. ¹H NMR: (DMSO) δ(ppm): 10.74 (bs,1H), 9.61 (bs, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.41 (d, J=7.9 Hz, 2H), 7.17(d, J=7.5 Hz, 1H), 6.99-6.85 (m, 5H), 6.78 (d, J=7.5 Hz, 1H), 6.60 (dd,J=7.0, 7.0 Hz, 1H), 4.92-4.89 (m, 3H), 3.29-3.23 (m, 1H), 3.15-3.07 (m,1H). MS: (calc.) 373.1; (obt.) 374.1 (MH)⁺.

Example 162

[0617] Step 1: Methyl 4-(1-oxo-indan-2-ylmethyl)-benzoate (271)

[0618] A 2M LDA solution in THF (4.16 ml, 8.32 mmol) was added to asolution of indanone (1.00 g, 7.57 mmol) in THF (10 ml) at −60° C. Thesolution was slowly warmed to 0° C. during a period of 15 min. and wasagitated for 15 more min. The reaction was then cooled to −78° C. and asolution of methyl-4-bromobenzoate (1.73 g, 7.57 mmol) was slowly added.The solution was slowly warmed to −20° C. and stirred during 4 hours.The reaction mixture was quenched with HCL 1M and the solvent wasevaporated. The residue was diluted in ethyl acetate, washed with brine,dried over anhydrous MgSO₄, filtered and concentrated. The crude residuewas then purified by flash chromatography on silica gel (5-20%AcOEt/HEx)to afford the title compound 271 (245 mg, 17%) as a whitesolid. LRMS: 280.1 (Calc.); 281.1 (found).

[0619] Step 2: N-(2-Amino-phenyl)-4-(1-oxo-indan-2-ylmethyl)-benzamide(272)

[0620] The title compound 272 was obtained following the same procedureas Example 1, step 4, 5. ¹H NMR: (DMSO) δ(ppm): 9.59 (bs, 1H), 7.91 (d,J=7.6 Hz, 2H), 7.69-7.64 (m, 2H), 7.54 (d, J=7.6 Hz, 1H), 7.45-7.40 (m,3H), 7.16 (d, J=8.2 Hz, 1H), 6.96 (dd, J=7.3, 7.3 Hz, 1H), 6.77 (d,J=8.2 Hz, 1H), 6.59 (dd, J=7.3, 7.3 Hz, 1H), 4.87 (bs, 2H), 3.23-3.14(m, 3H), 2.85-2.81 (m, 2H). LRMS: 356.1 (calc.); 357.2 (found).

Example 163

[0621] Step 1: 4-(1-Oxo-indan-2-ylidenemethyl)-benzoic acid (273)

[0622] To a suspension of indanone (2.00 g, 15.1 mmol) and4-carboxybenzaldehyde (1.89 g, 12.6 mmol) in EtOH (10 ml) was added KOH(1.77 g , 31.5 mmol) at 0° C. The reaction mixture was stirred 30 min at0° C. then at room temperature for 16 h. The solvent was evaporated andthe residue was dissolved in water, acidified to pH 5 with HCl 1 M. Theprecipitate was filtered and rinsed with water to afford the titlecompound 273 (2.27 g, 57%) as a yellow solid. LPMS: 264.1 (Calc.); 265.0(found).

[0623] Step 2:N-(2-Amino-phenyl)-4-(1-oxo-indan-2-ylidenemethyl)-benzamide (274)

[0624] The title compound 274 was obtained following the same procedureas Example 1, step 5. LRMS: 354.1 (Calc.); 355.0 (found).

[0625] Step 3:N-(2-Amino-phenyl)4-(1-hydroxy-indan-2-ylmethyl)-benzamide (275)

[0626] To a suspension of 274 (300 mg, 0.85 mmol) in MeOH (8 ml) andwater (1 ml) was added NaBH₄ (75 mg, 1.95 mmol). The reaction mixturewas stirred at 50° C. 16 h and cooled down. Water was added to thesolution and the precipitated was filtered and rinsed with cold water toafford the title compound 275 (224 mg, 74%) as a white solid. ¹H NMR:(acetone) δ(ppm): 9.05 (bs, 1H), 8.00 (dd, J=8.2, 2.7 Hz, 2H), 7.47 (d,J=8.5 Hz, 1H), 7.43 (d, J=8.2 Hz, 1H), 7.38-7.30 (m, 2H), 7.22-7.12 (m,3H), 7.01 (ddd, J=7.6, 7.6, 1.5 Hz, 1H), 6.87 (dd, J=8.0, 1.1 Hz, 1H),6.68 (dd, J=7.6, 7.6 Hz, 1H), 4.98 (t, J=5.8 Hz, 0.4H), 4.89 (t, J=6.7Hz, 0.6H), 4.63 (bs, 2H), 4.45 (d, J=6.9 Hz, 0.6H), 4.06 (d, J=6.0 Hz,0.4H), 3.30-3.19 (m, 1H), 2.88-2.48 (m, 3H, CH₂). LRMS: 358.2 (calc.);359.1 (found).

Example 164

[0627] Step 1: 4-(3.5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-benzoicacid (276)

[0628] To a solution of NaH (60% in mineral oil, 250 mg, 6.3 mmol) at 0°C. acetyl acetone (0.646 ml, 6.3 mmol) was added followed by4-bromomethyl-benzoic acid methyl ester 2 (1.2 g, 5.2 mmol). Thereaction mixture stirred 1 hour at room temperature and refluxed for 2hours. Phenyl hydrazine (0.51 ml, 5.2 mmol) was added and the reactionmixture refluxed for an additional hour. THF was removed in vacuum andthe oily residue was partitioned between water and ethyl acetate.Organic layer was separated, dried, evaporated and purify bychromatography on a silica gel column, eluent EtOAc-hexane (1:1) toproduce an oily material (800 mg) which was treated with a solution ofNaOH (0.8 g, 20 mmol) in 20 ml water for 1 hour at room temperature. Thefollowing steps, acidification with HCl (pH 6), extraction of theresultant emulsion with ethyl acetate, drying the extract with sodiumsulfate, evaporation and column chromatography (eluent EtOAc-hexane,1:1) afforded 390 mg of a mixture of 276 (the title compound) and 278(molar ratio 1:2) [M−1]⁺ 307.0 and 191.1 This mixture was taken for thenext step as is.

[0629] Step 2.N-(2-Amino-phenyl)-4-(3,5-dimethyl-1-phenyl-1H-pyrazol4-ylmethyl)-benzamide(277)

[0630] Following a procedure analogous to that described in Example 92,step 2, but substituting 276 for 143, the title compound 277 wasobtained in 25% yield (purified by chromatography using as eluentEtOAc-hexane, 1:1). ¹H NMR: (300 MHz, DMSO-d₆, δ(ppm): 9.64 (s, 1H);7.97 (d, J=7.6 Hz, 2H), 7.42-7.56 (m, 5H), 7.37 (d, J=8.2 Hz, 2H), 7.22(d, J=7.6 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 6.84 (d, J=8.2 Hz, 1H), 6.66(t, J=7.6 Hz, 1H), 4.93 (s, 2H), 3.92 (s, 2H), 2.34 (s, 3H), 2.18 (s,3H).

Example 165

[0631] Step 1: 4-(3-Oxo-butyl)-benzoic acid (278)

[0632] To a solution of acetyl acetone (5.0 ml, 49 mmol) at roomtemperature NaOMe (25% wt, 10.8 ml, 47.3 mmol) was added followed by4-bromomethyl-benzoic acid methyl ester 2 (9.0 g, 39.3 mmol). Thereaction mixture refluxed 3 hours, cooled to the room temperature andacidified with HCl (pH 1-2). Evaporation of the resultant solutionyielded a residue, which was refluxed in a mixture of glacial AcOH (50ml) and conc. HCl (25 ml) for 4 hours. Acids were removed in vacuum andthe residue was triturated with water to form a crystalline material,which was collected by filtration and dried to afford 278 (6.72 g, 80%yield). [M−1] 191.1.

[0633] Step 2. 4-(5-Amino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoicacid 279

[0634] To a refluxing suspension of 4-(3-oxo-butyl)-benzoic acid 278(700 mg, 3.65 mmol), malonodinitrile (241 mg, 3.65 mmol) and sulfur (130mg, 3.65 mmol) in 20 ml EtOH, diethylamine (0.5 ml, 4.8 mmol) was added.The reaction mixture refluxed 1 hour, cooled to the room temperature,acidified with conc. HCl (pH 4-5) and evaporated to yield a solidresidue. This material was partitioned between water and ethyl acetate,organic layer was separated, dried, evaporated and chromatographed on asilica gel column, eluent EtOAc-hexane, 1:1, to afford the titlecompound 279 (300 mg, 30% yield). ¹H NMR: (300 MHz, DMSO-d₆, δppm): 7.87(d, J=8.4 Hz, 2H), 7.29 (d, J=7.9 Hz, 2H), 6.98 (s, 2H), 3.92 (s, 2H),2.03 (s, 3H).

[0635] Step 3.4-(5-Acetylamino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic acid 280

[0636] To a solution of4-(5-amino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzoic acid 279 (230mg, 0.86 mmol) in a solvent mixture acetone (5 ml)-dichloromethane (5ml) at room temperature acetyl chloride (0.305 ml, 4.3 mmol) was added.After 2 hours of stirring at the same conditions a precipitate of thetitle compound 280 formed which was collected and dried (200 mg, 75%yield). [M−1] 313.1.

[0637] Step 4:N-(2-Amino-phenyl)4-(5-acetylamino-4-cyano-3-methyl-thiophen-2-ylmethyl)-benzamide(281)

[0638] Following a procedure analogous to that described in Example 92,step 2, but substituting 280 for 143, the title compound 281 wasobtained in 25% yield. 1H NMR (DMSO) δ(ppm): 9.61 (s, 1H); 7.91 (d,J=7.9 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.15 (d, J=7.5 Hz, 1H), 6.96 (t,J=6.6 Hz, 1H), 6.77 (d, J=7.0 Hz, 1H), 6.59 (t, J=7.9 Hz, 1H), 4.89 (s,2H), 4.10 (s, 2H), 2.19 (s, 3H), 2.16 (s, 3H). [M+1] 405.0.

Example 166

[0639] Step 1. 4-(N-Hydroxycarbamimidoylmethyl)-benzoic acid (282)

[0640] A suspension of 4-cyanomethyl benzoic acid (2.07 g, 12.86 mmol),NH₂OH.HCl (1.79 g, 25.71 mmol) and potassium hydroxide (2.16 g, 38.57mmol) in 70 ml ethanol refluxed for 36 hours, poured into 100 ml waterand acidified with conc. HCl (pH 5-6). EtOH was removed in vacuum andthe remaining suspension was treated with another 100 ml water. Aprecipitate formed which was collected and dried to afford the titlecompound 282. [M+1]195.1.

[0641] Step 2. 4-(5-Methyl-[1,2,4]oxadiazol-3-ylmethyl)-benzoic acid(283)

[0642] A solution of 4N-hydroxycarbamimidoylmethyl)-benzoic acid 282(388 mg, 2.0 mmol) in pyridine (8 ml) was treated with acetic anhydride(0.283 ml, 3.0 mmol). The resultant solution refluxed 6 hours,evaporated in vacuum and the remaining solid was triturated with water,collected by filtration, dried and purified by chromatography on asilica gel column, eluent EtOAc, EtOAc-MeOH (10:1) and finallyEtOAc-MeOH (1:1), to produce 283 (164 mg, 38% yield).[M−1]⁻217.1

[0643] Step 3.N-(2-Amino-phenyl)-4-(5-methyl-[1,2,4]oxadiazol-3-ylmethyl)-benzamide(284)

[0644] For the preparation of the title compound 284, a procedureanalogous to that described in Example 92, step 2, but substituting 283for 143, the title compound 284 was obtained. ¹H NMR: (DMSO) δ(ppm):9.62 (s, 1H), 7.93 (d, J=7.9 Hz, 2H), 7.42 (d, J=8.4 Hz, 1H), 7.16 (d,J=7.5 Hz, 1H), 6.97 (t, J=7.9 Hz, 1H), 6.78 (d, J=7.5 Hz, 1H), 6.60 (t,J=7.9 Hz, 1H), 4.92 (s 2H), 4.14 (s, 2H), 2.55 (s, 3H). [M+1]⁺ 309.2

Example 167

[0645] Step 1: 4-(3.5-Dimethyl-pyrazol-1-yl)-benzoic acid (285)

[0646] A solution of 4-hydrazino-benzoic acid (0.60 g, 3.95 mmol) andacetyl acetone (0.405 ml, 3.95 mmol) in ethanol (20 ml) refluxed for 1hour. Ethanol was removed in vacuum and the remaining solid wastriturated with water and collected by filtration to produce 285 (0.71mg, 83% yield). [M−1]⁻ 215.1.

[0647] Step 2. N(2-Amino-phenyl)-4-(3,5-dimethyl-pyrazol-1-yl)-benzamide(286)

[0648] For the preparation of the title compound 286, a procedureanalogous to that described in Example 92, step 2, but substituting 285for 143, the title compound 286 was obtained in 34% yield (purified bychromatography using as eluent CH₂Cl₂-methanol, 19:1). ¹H NMR: (DMSO)δ(ppm): 9.73 (s, 1H); 8.09 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.4 Hz, 2H),7.17 (d, J=7.5 Hz, 1H), 6.98 (t, J=7.0 Hz, 1H), 6.78 (d, J=7.9 Hz, 1H),6.60 (t, J=7.5 Hz, 1H), 6.13 (s, 1H), 4.92 (s, 2H), 2.37 (s, 3H), 2.20(s, 3H). [M+1]⁺ 303.3

Example 168

[0649] Step 1: 2-(3,4,5-Trimethoxy-phenyl)-2,3-dihydro-furan (287)

[0650] To a solution of 5-iodo-1,2,3-trimethoxybenzene (900 mg, 3.06mmol) and 2,3-dihydrofuran (1.16 mL, 15.3 mmol) in dry DMF (8 mL) wereadded PPh₃ (20 mg, 0.077 mmol), KOAc (901 mg, 9.18 mmol), n-Bu₄NCl (850mg, 3.06 mmol) and Pd(OAc)₂ (17 mg, 0.077 mmol). The reaction mixturewas stirred 18 h at 80° C. The reaction mixture was diluted with AcOEtand water. After separation, the organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was then purified by flash chromatography on silica gel(AcOEt/Hexane: 20/80) to afford the title compound 287 (311 mg, 1.32mmol, 43% yield). ¹H NMR: (300 MHz, CDCl₃) δ(ppm): 6.59 (s, 2H), 6.45(m, 1H), 5.45 (dd, J=10.5, 8.4 Hz, 1H), 4.97 (m, 1H), 3.87 (s, 6H), 3.84(s, 3H), 3.06 (m, 1H), 2.62 (m, 1H).

[0651] Step 2:4-[5-(3,4,5-Trimethoxy-phenyl)-2,5-dihydro-furan-2-yl]-benzoic acidethyl ester (288)

[0652] To a solution of 287 (200 mg, 0.846 mmol) and 4-lodo-benzoic acidethyl ester (468 mg, 1.69 mmol) in dry acetonitrile (4 mL) were addedPPh₃ (20 mg, 0.076 mmol), Ag₂CO₃ (467 mg, 1.69 mmol) and Pd(OAc)₂ (7 mg,0.03 mmol). The reaction mixture was stirred 18 h at 80° C. The reactionmixture was filtered through celite and washed with AcOEt. Water wasadded and the phases were separated. The organic layer was washed withbrine, dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was then purified by flash chromatography on silica gel(AcOEt/Hexane: 30/70) to afford the title compound 288 (280 mg, 0.728mmol, 86% yield). ¹H NMR (300 MHz, CDCl₃) δ(ppm): 8.05 (d, J=7.5 Hz,2H), 7.45 (d, J=7.5 Hz, 2H), 6.18-5.95 (m, 4H), 4.38 (q, J=7.0 Hz, 2H),3.88 (s, 6H), 3.84 (s, 3H), 1.39 (t, J=7.0 Hz).

[0653] Step 3:N-(2-Amino-phenyl)4-[5-(3,4,5-trimethoxy-phenyl)-2,5-dihydro-furan-2-yl]-benzamide(289)

[0654] Following a procedure analogous to that described in Example 1,step 4, 5, but substituting 288 for 6, the title compound 289 wasobtained in 48% yield. ¹H NMR (DMSO) δ(ppm): 8.00 (s, 1H), 7.91 (d,J=7.9 Hz, 2H), 7.48 (d, J=7.9 Hz, 2H), 7.33 (d, J=7.5 Hz, 1H), 7.09 (t,J=7.5 Hz, 1H), 6.92-6.82 (m, 2H), 6.61 (s, 2H), 6.14-5.99 (m, 4H), 3.89(s, 6H), 3.84 (s, 3H).

Example 169

[0655] Step 1:N-(2-Amino-phenyl)4-[5-(3,4,5-trimethoxy-phenyl)-tetrahydro-furan-2-yl]-benzamide.(290)

[0656] To a degazed solution of 289 (43 mg, 0.096 mmol) in AcOEt (4 mL)was added PtO₂ (3 mg, 0.01 mmol) and the reaction mixture was stirred atroom temperature under a 1 atm pressure of H₂ for 16 h. The reactionflask was purged with N₂ then the reaction mixture was filtered throughcelite, rinsed with MeOH and concentrated. The crude residue waspurified three times by flash chromatography on silica gel (MeOH/DCM:2/98, AcOEt/DCM: 30/70 and AcOEt/CHCl₃: 30/70) to afford the titlecompound 290 (10 mg, 0.22 mmol, 23% yield).¹H NMR (CDCl₃) δ(ppm): 8.10(s, 1H), 7.91 (d, J=8.0 Hz, 2H), 7.50 (d, J=8.0 Hz, 2H), 7.34 (d, J=7.5Hz, 1H), 7.10 (t, J=7.5 Hz, 1H), 6.96-6.85 (m, 2H), 6.64 (s, 2H), 5.33(t, J=7.0 Hz, 1H), 5.21 (t, J=7.0 Hz, 1H), 3.89 (s, 6H) 3.85 (s, 3H),2.59-2.40 (m, 2H), 2.09-1.88 (m, 2H).

Example 169

[0657] Step 1: [2-(4-Vinyl-benzoylamino)-phenyl]-carbamic acidtert-butyl ester (291)

[0658] Following a procedure analogous to that described in Example 143,step 2, but substituting 184 for 221, the title compound 291 wasobtained in 90% yield as a dark yellow oil. ¹H NMR: (300 MHz, CDCl₃)δ(ppm): 9.18 (s, 1H), 7.94 (d, J=8.5 Hz, 2H), 7.77 (d, J=7.77 (d, J=7.5Hz, 1H), 5.87 (d, 7.49 (d, J=8.5 Hz, 2H), 7.30-7.10 (m, 3H), 6.89 (s,1H), 6.77 (dd, J=17.4, 11.0 Hz, 1H), 5.87 (d, J=17.4 Hz, 1H), 5.39 (d,J=11.0 Hz, 1H), 1.52 (s, 9H).

[0659] Step 2: [2-(4-Oxiranyl-benzoylamino)-phenyl]-carbamic acidtert-butyl ester (292)

[0660] To a solution of 291 (4.1 g, 12.1 mmol) in dry CHCl₃ (60 mL) wasadded m-CPBA 70% (3.6 g, 14.5 mmol). The reaction mixture was stirred atroom temperature for 5 h then additional m-CPBA (0.6 g, 2.4 mmol) wasadded and the stirring continued for 1 h. A further amount of m-CPBA(0.6 g, 2.4 mmol) was added and the reaction mixture was stirred for 16h. Chloroform and a 10% solution of NaHCO₃ were added and the phaseswere separated. The organic layer was washed with water and brine, driedover anhydrous Na₂SO₄, filtered and concentrated. The crude residue wasthen purified by flash chromatography on silica gel (AcOEt/Hexane: 1/3)to afford the title compound 292 (2.86 g, 8.07 mmol, 66% yield). ¹H NMR(300 MHz, CDCl₃) δ(ppm): 9.20 (s, 1H), 7.95 (d,J=8.1 Hz, 2H), 7.86-7.75(m, 1H), 7.38 (d, J=8.1 Hz, 2H), 7.26-7.10 (m, 3H), 6.84-6.70 (m, 1H),3.93 (t, J=3.0 Hz, 1H), 3.20 (t, J=5.0 Hz, 1H), 2.80 (dd, J=5.0, 3.0 Hz,1H), 1.52 (s, 9H).

[0661] Step 3:(2-{4-[1-Hydroxy-2-(3,4,5-trimethoxy-phenylamino)-ethyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (295) and(2-{4-[2-Hydroxy-1-(3,4,5-trimethoxy-phenylamino)-ethyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (293)

[0662] To a stirred solution of CoCl₂ (8 mg, 0.06 mmol) in dryacetonitrile (10 mL) was added 292 (1 g, 2.8 mmol) followed by3,4,5-trimethoxyaniline (516 mg, 2.8 mmol) and the reaction mixture wasallowed to react for 16 h at room temperature then it was heated at 60°C. for 5 h. The reaction mixture was partitioned between AcOEt and waterand the phases were separated. The organic layer was washed with brine,dried over anhydrous Na₂SO₄, filtered and concentrated. The cruderesidue was purified by flash chromatography on silica gel(AcOEt/Hexane: 1/1) to afford compounds 293 and 295 (combined: 1.07 g,1.99 mmol, 71% yield, ratio 292/295=5/1) which can be separated by flashchromatography on silica gel (AcOEt/Hexane: 1/1). ¹H NMR (300 MHz,CDCl₃) δ(ppm): Compound 292: 9.21 (s, 1H), 7.92 (d, J=8.1 Hz, 2H), 7.73(d, J=6.6 Hz, 1H), 7.46 (d, J=8.1 Hz, 2H), 7.28-7.10 (m, 3H), 6.90 (s,1H), 5.83 (s, 2H), 4.54-4.44 (m, 1H), 3.93 (dd, J=8.1, 3.9 Hz, 1H),3.84-3.72 (m, 1H), 3.71 (s, 3H), 3.66 (s, 6H), 1.47 (s, 9H). Compound295: 9.22 (s, 1H), 7.91 (d, J=8.1 Hz, 2H), 7.77 (d, J=7.2 Hz, 1H), 7.46(d, J=8.1 Hz, 2H), 7.30-7.21 (m, 3H), 6.88 (s, 1H), 6.15 (s, 2H),5.16-5.06 (m, 1H), 3.81 (s, 6H), 3.78 (s, 3H), 3.50-3.25 (m, 2H), 1.51(s, 9H).

[0663] Step 4:N-(2-Amino-phenyl)-4-[2-hydroxy-1-3,4,5-trimethoxy-phenylamino)-ethyl]-benzamide(294)

[0664] Following a procedure analogous to that described in Example 42,step 3, but substituting 293 for 46, the title compound 294 was obtainedin 50% yield. ¹H NMR (DMSO) δ(ppm): 8.36 (s, 1H), 7.74 (d, J=6.9 Hz,2H), 7.30 (d, J=7.8 Hz, 2H), 7.18 (d, J=6.9 Hz, 12H), 7.00 (t, J=7.2 Hz,1H), 6.72 (m, 2H), 5.69 (s, 2H), 4.34 (m, 1H), 4.02-3.52 (m, 2H), 3.66(s, 3H), 3.57 (s, 6H).

Example 170

[0665] Step 1:N-(2-Amino-phenyl)-4-[2-oxo-343.4,5-trimethoxy-phenyl)-oxazolidin-4-yl]-benzamide(296)

[0666] To a solution of 293 (200 mg, 0.372 mmol) in toluene (5 mL) andTHF (1 mL) was added 1,1′-carbonyldiimidazole (72 mg, 0.45 mmol)followed by Et₃N (156 μL, 1.12 mmol) and the mixture was stirred at roomtemperature for 5 h then at 90° C. for 48 h. The reaction mixture wasdiluted with AcOEt, a solution of sat. NH₄Cl was added and the phaseswere separated. The organic layer was washed with brine, dried overanhydrous Na₂SO₄, filtered and concentrated. The crude residue waspurified by flash chromatography on silica gel (DCM/AcOEt: 80/20) toafford the desired compound (120 mg, 0.21 mmol, 57% yield). ¹H NMR(DMSO) δ(ppm): 9.37 (s, 1H), 7.98 (d, J=8.1 Hz, 2H), 7.76 (d, J=7.5 Hz,1H), 7.41 (d, J=8.1 Hz, 2H), 7.25-15 (m, 3H), 6.88 (s, 1H), 6.61 (s,2H), 5.40 (dd, J=8.7, 6.0 Hz, 1H), 4.79 (t, J=8.7 Hz, 1H), 4.19 (dd,J=8.7, 6.0 1H), 3.75 (s, 3H), 3.72 (s, 6H), 1.47 (s, 9H).

[0667] Following a procedure analogous to that described in Example 42,step 3, but substituting the previous compound for 46, the titlecompound 296 was obtained in 81% yield.). ¹H NMR (DMSO) δ(ppm): 8.03 (s,1H), 7.91 (d, J=8.1 Hz, 2H), 7.41 (d, J=8.1 hz, 2H), 7.30 (d, J=7.5 Hz,1H), 7.07 (t, J=7.5 Hz, 1H), 6.82 (d, J=7.5 Hz, 2H), 6.61 (s, 2H) 5.40(dd, J=8.7, 6.0 Hz, 1H), 4.78 (t, J=8.7 Hz, 1H), 4.18 (dd, J=8.7, 6.0Hz, 1H), 3.75 (s, 3H), 3.71 (s, 6H).

Example 171

[0668] Step 1:N-(2-Amino-phenyl)-4-[2-oxo-3-3,4,5-trimethoxy-phenyl)-oxazolidin-5-yl]-benzamide(297)

[0669] To a solution of 295 (130 mg, 0.242 mmol) in DCM (2 mL) was added1,1′-carbonyldiimidazole (47 mg, 0.29 mmol) and the mixture was stirredat room temperature for 16 h. DCM was removed under reduced pressure,AcOEt and a solution of sat. NH₄Cl were added and the phases wereseparated. The organic layer was washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. The crude residue was purified byflash chromatography on silica gel (Hexane/AcOEt: 30/70) to afford thedesired compound (80 mg, 0.14 mmol, 58% yield). ¹H NMR (DMSO) δ(ppm):9.39 (s, 1H), 8.04 (d, J=8.1 Hz, 2H), 7.84 (d, J=7.5 Hz, 1H), 7.52(d,J=8.1 Hz, 2H), 7.26-7.12 (m, 3H), 6.86-6.74 (m, 3H), 5.70 (t, J=8.4Hz, 1H), 4.24 (t, J=8.7 Hz, 1H), 3.97-3.87 (m, 1H), 3.87 (s, 6H), 3.82(s, 3H), 1.52 (s, 9H).

[0670] Following a procedure analogous to that described in Example 42,step 3, but substituting the previous compound for 46, the titlecompound 297 was obtained in 94% yield.). ¹H NMR (DMSO) δ(ppm): 8.38 (s,1H), 7.97 (d, J=7.5 Hz, 2H), 7.47 (d, J=8.1 Hz, 2H), 7.35 (d, J=7.0 Hz,1H), 7.08 (t, J=7.0 Hz, 1H), 6.97-6.87 (m, 2H), 6.79 (s, 2H), 5.66 (t,J=8.1, 1H), 4.41 (t, J=9.0 Hz, 1H), 3.91 (t, J=7.8 Hz, 1H), 3.86 (s,6H), 3.82 (s, 3H).

Example 172

[0671] Step 1:{2-[4-(1-Azido-2-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester (298) and{2-[4-(2-Azido-1-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester (302)

[0672] To a solution of 292 (210 mg, 0.59 mmol) in acetonitrile (9 mL)and water (1 mL) was added CeCl₃ heptahydrate (110 mg, 0.296 mmol)followed by NaN₃ (42 mg, 0.65 mmol). The reaction mixture was refluxedfor 3 h then acetonitrile was removed under reduced pressure. Theresidue was diluted with DCM, washed with brine, dried over anhydrousNa₂SO₄, filtered and concentrated. Purification by flash chromatographyon silica gel (AcOEt/Hexane: 1/1) afforded a 1:1 mixture of titlecompounds 298 and 302 (combined: 187 mg, 0.47 mmol, 80% yield) whichwere separated by flash chromatography on silica gel (AcOEt/Hexane:2/5). Compound 298: ¹H NMR: (300 MHz, CDCl₃/CD₃OD) δ(ppm): 7.95 (d,J=8.1 Hz, 2H), 7.70-7.63 (m, 1H), 7.43 (d, J=8.1 Hz, 2H), 7.36-7.29 (m,1H), 7.24-7.14 (m, 2H), 4.69 (dd, J=7.5, 4.8 Hz, 1H), 3.80-3.65 (m, 2H),1.49 (s, 9H). Compound 302: ¹H NMR: (300 MHz, CDCl₃) δ(ppm): 9.28 (s,1H), 7.86 (d, J=8.4 Hz, 2H), 7.71 (d, J=7.5 Hz, 1H), 7.38 (d, J=8.4 Hz,2H), 7.25-7.08 (m, 3H), 7.01 (s, 1H), 4.87 (dd, J=6.9, 5.1 Hz, 1H),3.47-3.38 (m, 2H), 3.32-3.21 (bs, 1H), 1.50 (s, 9H).

[0673] Step 2:{2-[4-(1-Amino-2-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester (299)

[0674] To a solution of 298 (156 mg, 0.39 mmol) in MeOH (2 mL) was addedPd/C 10% (20 mg, 0.02 mmol). The reaction mixture was stirred under a 1atm pressure of H₂ at room temperature for 16 h then it was purged withN₂. The palladium was removed by filtration through celite and the MeOHwas evaporated under reduced pressure to afford the title compound 299(88 mg, 0.24 mmol, 60% yield), which was used without purification. ¹HNMR (300 MHz, CDCl₃) δ(ppm): 9.24 (s, 1H), 7.90 (d, J=7.8 Hz, 2H), 7.71(d, J=6.6 Hz, 1H), 7.40 (d, J=7.8 Hz, 2H), 7.31-7.10 (m, 3H), 7.06-6.94(m, 1H), 4.12 (dd, J=7.5, 4.5 Hz, 1H), 3.74 (dd, J=7.8, 5.4 Hz, 1H),3.64-3.51 (m, 1H), 2.64 (s, 3H), 1.49 (s, 9H).

[0675] Step 3:(2-{4-[(3,4-Dimethoxy-benzoylamino)-2-hydroxy-ethyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (300)

[0676] To a stirred solution of 299 (88 mg, 0.24 mmol) in dry DCM (2 mL)at −20° C. was added 3,4-dimethoxybenzoyl chloride (50 mg, 0.25 mmol)followed by Et₃N (37 μL, 0.26 mmol). The reaction mixture was allowed towarm up to room temperature then was stirred for 48 h. A solution ofsat. NH₄Cl was added, followed by DCM and the phases were separated. Theorganic layer was washed with brine, dried over anhydrous Na₂SO₄,filtered and concentrated. The crude residue was purified by flashchromatography on silica gel (MeOH/DCM: 4/96) to afford title compound300 (91 mg, 0.17 mmol, 71% yield). ¹H NMR (300 MHz, CDCl₃) δ(ppm): 9.29(s, 1H), 7.81 (d, J=8.1 Hz, 2H), 7.65-7.58 (m, 1H), 7.46 (m, 7H), 6.80(d, J=8.1 Hz, 1H), 5.20-5.10 (m, 1H), 3.95-3.78 (m, 2H), 3.88 (s, 3H)3.84 (s, 3H), 1.47 (s, 9H).

[0677] Step 4:N-(2-Amino-phenyl-4-[2-(3,4-dimethoxy-phenyl)-4,5-dihydro-oxazol-4-yl]-benzamide(301)

[0678] To a solution of 300 (91 mg, 0.17 mmol) in dry THF (2 mL) wasadded the Burgess reagent (44 mg, 0.19 mmol) and the mixture was stirredat 70° C. for 2 h. The reaction mixture was partitioned between AcOEtand water and the phases were separated. The organic layer was washedwith brine, dried over anhydrous Na₂SO₄, filtered and concentrated. Thecrude residue was purified by flash chromatography on silica gel(MeOH/DCM: 3/97) to afford the Boc-protected intermediate (75 mg, 0.14mmol, 85% yield). ¹H NMR (CDCl₃) δ(ppm): 9.31 (s, 1H), 7.94 (d, J=8.4Hz, 2H), 7.72 (d, J=7.5 Hz, 1H), 7.66 (d, J=8.1 Hz, 1H), 7.61 (s, 1H),7.39 (d, J=8.1 Hz, 2H), 7.27 (d, J=6.0 Hz, 1H), 7.23-7.08 (m, 3H), 6.93(d, J=8.7 Hz, 1H), 5.43 (t, J=9.0 Hz, 1H), 4.84 (t, J=9.3 Hz, 1H), 4.26(t, J=8.4 Hz, 1H), 3.95 (s, 3H), 3.94 (s, 3H), 1.50 (s, 9H).

[0679] Following a procedure analogous to that described in Example 42,step 3, but substituting the previous compound for 46, the titlecompound 301 was obtained in 82%. ¹H NMR (CDCl₃) δ(ppm): 8.01 (s, 1H),7.89 (d, J=7.9 Hz, 2H), 7.65 (dd, J=8.4, 1.5 Hz, 1H), 7.60 (d, J=1.5 Hz,1H), 7.41 (d, J=7.9 Hz, 2H), 7.32 (d, J=7.9 Hz, 1H), 7.08 (t, J=6.6 Hz,1H), 6.92 (d, J=8.4 Hz, 1H), 6.84 (d, J=7.9 Hz, 2H), 5.43 (dd, J=9.7,8.4 Hz, 1H), 4.83 (dd, J =9.7, 8.4 Hz, 1H), 4.25 (t, J=8.1 Hz, 1H), 3.94(s, 3H), 3.93 (s, 3H).

Example 173

[0680] Step 1:{2-[4-(2-Amino-1-hydroxy-ethyl)-benzoylamino]-phenyl}-carbamic acidtert-butyl ester (303)

[0681] The title compound 303 was obtained in 94% yield from 302following the same procedure as in Example 172, step 2. The compound 303was used directly for next step without purification.

[0682] Step 2:2-{4-[2-(3,4-Dimethoxy-benzoylamino)-1-hydroxy-ethyl]-benzoylamino}-phenyl)-carbamicacid tert-butyl ester (304)

[0683] The title compound 304 was obtained in 40% yield from 303 and3,4-dimethoxybenzoyl chloride following the same procedure as in Example172, step 3. ¹H NMR (CDCl₃) δ(ppm): 9.31 (s, 1H), 7.78 (d, J=8.1 Hz,2H), 7.68 (d, J=6.9 Hz, 1H), 7.38 (d, J=1.8 Hz, 1H), 7.33 (d, J=8.1 Hz),7.30-7.06 (m, 4H), 7.00-6.93 (m, 1H), 6.79 (d, J=8.4 Hz, 1H),4.89-4.89-4.82 (m, 1H), 3.88 (s 3H), 3.86 (s, 3H), 3.85-3.73 (m, 1H),3.44-3.32 (m, 1H), 1.46 (s, 9H).

[0684] Step 3:N-(2-Amino-phenyl)-4-[2-(3,4dimethoxy-phenyl)-4,5-dihydro-oxazol-5-yl]-benzamide(305)

[0685] Following a procedure analogous to that described in Example 172,step 4, 5, but substituting 304 for 300, the title compound 305 wasobtained in 63%. ¹H NMR (CDCl₃) δ(ppm): 8.02 (s, 1H), 7.93 (d, J=8.1 Hz,2H), 7.63 (dd, J=8.4, 1.8 Hz, 1H), 7.60 (s, 1H), 7.44 (d, J=8.1 Hz, 2H),7.33 (d, J=7.5 Hz, 1H), 7.09 (t, J=7.5 Hz, 1H), 6.91 (d, J=8.1 Hz, 1H),6.85 (d, J=8.1 Hz, 2H), 5.74 (dd, J=10.0, 7.8 Hz, 1H), 4.51 (dd, J=14.5,10.0 Hz, 1H), 4.00-3.90 (m, 7H).

Example 178

[0686] STEP 1: [2-(4-FORMYL-BENZOYLAMINO)-PHENYL]-CARBAMIC ACIDTERT-BUTYL ESTER (315)

[0687] To a suspension of 4-carboxybenzaldehyde (6 g, 40 mmol) indichloromethane (10 mL) was added thionyl chloride (4.1 mL, 56 mmol, 1.4eq), followed by DMF (1 mL) dropwise. The mixture was refluxed for 4hours and excess of thionyl chloride and DMF were removed under reducedpressure. To a solution of (2-aminophenyl)-carbamic acid tert-butylester (8.32 g, 40 mmol, 1 eq) in dichloromethane (80 mL), stirred at 0°C., was added a suspension of 4-formyl benzoyl chloride indichloromethane (20 mL), followed by diisopropyl ethylamine (3.61 mL, 20mmol, 1 eq). The mixture was stirred for 30 minutes at 0° C. then atroom temperature for 30 minutes. The crude residue was diluted withdichloromethane (300 mL) and washed with water. The combined organiclayers were dried (MgSO₄), filtered and concentrated under vacuo. Thecrude residue was purified by column chromatography on silica gel(elution 20% ethyl acetate in hexane) to give 6.1 g (45% yield) ofanilide 315. ¹H NMR (CDCl₃): δ10.18 (s, 1H), 9.64 (brs, 1H), 8.20 (d,J=7.9 Hz, 2H), 8.06 (d, J=7.9 Hz, 2H), 7.96 (d, J=7.9 Hz, 1H), 7.28-7.38(m, 1H), 7.24 (d, J=4.4 Hz, 1H), 6.84 (s, 1H), 6.81 (d, J=8.8 Hz, 1H),1.58 (s, 9H).

[0688] Step 2:(2-{4-[(3,4-Dimethoxyphenylamino)-Methyl]-Benzoylamino}-Phenyl)-CarbamicAcid Tert-Butyl Ester (316)

[0689] Following a procedure analogous to that described in Example 144,step 3, but substituting the previous compound for 226, the titlecompound 316 was obtained in quantitative yield. ¹H NMR (CDCl₃): δ9.21(brs, 1H), 8.01 (d, J=7.9 Hz, 2H), 7.86 (d, J=7.0 Hz, 1H), 7.55 (d,J=8.3 Hz, 2H), 7.20-7.34 (m, 3H), 6.89 (brs, 1H), 6.81 (d, J=8.8 Hz,1H), 6.37 (d, J=2.2 Hz, 1H), 6.23 (dd, J=2.6, 8.3 Hz, 1H), 4.45 (s, 2H),3.89 (s, 3H), 3.88 (s, 3H), 1.58 (s, 9H).

[0690] Step 3:N-(2-Aminophenyl)-4-[1-(3.4-dimethoxyphenyl)-3-(4-methylsulfanylphenyl)-ureidomethyl]-benzamide317

[0691] To a solution of anilide 316 (500 mg, 1.047 mmol) inchloroform/THF (1:1, 10 mL) was added isocyanate (169 μL, 1.205 mmol,1.15 eq). The mixture was stirred overnight at room temperature undernitrogen and the crude residue was concentrated and purified by columnchromatography on silica gel (elution 40% ethyl acetate in hexane) togive 606 mg (90% yield) of the desired compound. ¹H NMR (CDCl₃): δ9.25(s, 1H), 7.96 (d, J=8.3 Hz, 2H), 7.85 (d, J=7.0 Hz, 1H), 7.44 (d, J=8.3Hz, 2H), 7.20-7.36 (m, 6H), 6.93 (d, J=3.5 Hz, 1H), 6.90 (s, 1H), 6.75(dd, J=2.2, 8.3 Hz, 1H), 6.68 (dd, J=2.6 Hz, 1H), 6.33 (s, 1H), 5.0 (s,2H), 3.97 (s, 1H), 3.85 (s, 3H), 2.51 (s, 3H), 1.57 (s, 9H).

[0692] Following a procedure analogous to that described in Example 42,step 3, but substituting the previous compound for 46, the titlecompound 317 was obtained in 85% yield. ¹H NMR (DMSO-d₆): δ10.14 (brs,1H), 7.99 (d, J=7.9 Hz, 2H), 7.93 (s, 1H), 7.49 (d, J=8.35 Hz, 4H), 7.39(d, J=7.5 Hz, 1H), 7.10-7.30 (2m, 5H), 6.97 (dd, J=2.2, 8.35 Hz, 1H),6.77 (dd, J=2.2, 8.35 Hz, 1H), 5.02 (s, 2H), 3.80 (s, 3H), 3.77 (s, 3H),2.48 (s, 3H).

Example 179

[0693] Step 1: N-(2-Amino-phenyl)-6-chloro-nicotinamide (318)

[0694] Following the procedure described in Example 42, step 2, thetitle compound 318 was obtained in 80% yield. LRMS=calc:246.69,found:247.7.

[0695] Step 2: N-(2-Amino-phenyl)-6-(quinolin-2-ylsulfanyl)-nicotinamide(319)

[0696] Following the procedure described in Example 45, step 1 butsubstituting 318 for 3,4,5-trimethoxybenzylamine, the the compound 319was obtained in 20% yield. ¹H NMR: (CD₃₀OD-d6) δ(ppm): 9.08 (d, J=1.9Hz, 1H), 8.35-8.25 (m, 2H), 7.99-7.56 (m, 7H), 7.23 (dd, J=1.2, 7.9 Hz,1H), 7.12 (dd J=1.4, 7.9, 14.0 Hz, 1H), 6.93 (dd, J=1.2, 8.0Hz, 1H),6.79 (ddd, J=1.2, 7.9 Hz, Hz, 1H).

[0697] Step 1: 4-[(4-Morpholin-4-yl-phenylamino)-methyl]-benzoic acid(402a)

[0698] A suspension of 4-formylbenzoic acid (2.53g; 16.8 mmol; 1 eq),4-morpholinoaniline (3g; 16.8 mmol; 1 eq) and BU₂SnCl₂ (510 mg; 1.68mmol; 0.1 eq) in dry THF (20 ml) was treated with PhSiH₃ (3.31 ml; 16.8mmol; 1 eq) at room temperature for 12 h. The reaction was filtered andthe solid product was washed with MeOH. The yield of the reaction was5.25g (99%). LRMS: calc 312.37; found: 313.2.

[0699] Step 2:N-(2-Amino-phenyl)-4-[(4-morpholin-4-yl-phenylamino)-methyl]-benzamide(402)

[0700] To a solution of acid 402a (2.61g; 8.36 mmol; 1 eq),1,2-phenylenediamine (903 mg; 8.36 mmol; 1 eq) and BOP (3.70 g; 8.36mmol; 1 eq) in dry DMF (20 ml) was added Et₃N (4.64 ml; 33.4 mmol; 4eq). After stirring overnight most of the DMF was removed under reducedpressure and chromatographed (Hex:EtAcO: 1:2/EtAcO). The crystal 402 wasobtained in 70% (2.35 g). ¹H-NMR (300.07 MHz; DMSO-d6) δ(ppm): 9.65 (s,1H), 7.97 (d, J=7.9, 2H), 7.53 (d, J=7.9, 2H), 7.22 (d, J=7.5, 1H), 7.03(dd, J=7.0, 7.5, 1H), 6.83 (d, J=7.9, 1H), 6.77 (d, J=8.8, 2H), 6.65(dd, J=7.5, 7.0,1H), 6.57 (d, J=8.8, 2H), 4.93 (bs, 2H), 4.36 (d, J=5.7,2H), 3.75 (m, 4H), 2.93 (m, 4H). LRMS: calc 402.49; found: 403.4.

Example 283a

[0701] Step 1. 4-[(3,4-Dimethoxyphenylamino)-methyl]-benzoic acid (424a)

[0702] In a 50 ml flask, a mixture of 4-aminoveratrole (1.53 g, 10mmol), 4-formyl-benzoic acid (1.50 g, 10 mmol), dibutyltin dichloride(304 mg, 1 mmol), phenylsilane (2.47 ml, 20 mmol) in anhydrous THF (10mL) and DMA (10 ml) was stirred overnight. at room temperature. Aftersolvents removal, the crude residue was dissolved in ethyl acetate (100ml) and then washed with saturated aqueous solution of NaHCO₃ (50 ml×3).The combined aqueous layers were acidified with 6% of NaHSO₄ to pH=4.The resulting white suspension was filtrated and then the filter cakewas washed with water (5 ml×3). The cake was dried over freeze dryer toafford acid (1.92 g, 67%) white solid product. LRMS=288 (MH)⁺.

[0703] Step 2.N-(2-Aminophenyl)-4-[(3,4-dimethoxyphenylamino)-methyl]-benzamide (424b)

[0704] In a 150 ml flask, a mixture of acid (1.92 g, 6.69 mmol),benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate(BOP, 3.26 g, 7.37 mmol), triethylamine (1.87 ml, 13.4 mmol),o-phenylenediamine (1.30 g, 12.02 mmol) in methylenechloride (67 ml) wasstirred at rt for 2 h. After solvents removal, the crude residue wasdissolved in EtOAc (100 ml) and then washed with NaHCO₃ saturatedsolution and brine 50 ml. The combined organic layers were dried overNa₂SO₄ and the filtrate was concentrated to dryness. The crude materialwas submitted to a chromatographic purification (column silica, 55%-70%EtOAc in 1% Et₃N of hexanes) and then the all interested fractions wereconcentrated to dryness. The residue was suspended in minimum quantitiesof ethyl acetate and then filtered to afford final product (1.49 g,59%). ¹H NMR (300 MHz, DMSO-d₆) δ(ppm): 9.65 (s, 1H), 7.98 (d, J=7.9 Hz,2H), 7.54 (d, J=7.9 Hz, 2H), 7.22 (d, J=7.9 Hz, 1H), 7.02 (dd, J=7.9,7.9 Hz, 1H), 6.83 (d, J=7.9 Hz, 1H), 6.72 (d, J=8.79 Hz, 1H), 6.45 (dd,J=7.5, 7.5 Hz, 1H), 6.39 (d, J=2.2 Hz, 1H), 6.01-6.08 (m, 2H), 4.94 (s,2H, NH₂), 4.36 (d, J=6.16 Hz, 2H), 3.72 (s, 3H), 3.65 (s, 3H).

Example 283b

[0705] Step 1:N-(4-Aminothiophen-3:yl)-4-[(3,4-dimethoxyphenylamino)-methyl]-benzamide:

[0706] Acid 424a (1040 mg; 3.62 mmol); 3,4-diaminothiophenedihydrochloride (1017 mg; 5.44 mmol; 1.50 eq.) and BOP (1770 mg; 4.0mmol; 1.1 eq.) were suspended in MeCN, treated with triethylamine (4 mL;29 mmol) and stirred for 18 h at room temperature; concentrated andpurified by chromatographic column on silica gel (elution 50% EtOAc inDCM) to render 527 mg (1.37 mmol; 38% yield) of compound 424c which was90% pure. 1H-NMR (300.07 MHz; DMSO-d6) δ(ppm): 8.56 (s, 1H), 7.78 (d,J=7.9 Hz, 2H), 7.43 (d, J=3.5 Hz, 1H), 7.38 (d, J=7.9 Hz, 2H) 6.73 (d,J=8.8 Hz, 1H), 6.33 (d, J=3.5 Hz, 1H), 6.58 (d, J=2.6 Hz, 1H), 6.13 (dd,J=2.6, 8.3 Hz, 1H), 4.33 (s, 2H), 3.80 (s, 3H), 3.78 (s, 3H). LRMS:calc: 383.4642; found: 384.2 (M+H); 406.2 (M+Na) and 192.6 (M+2H)/2.

[0707] Step 1: Methyl-(5-nitrobenzothiazol-2-yl)-amine (456a)

[0708] A mixture of 2-fluoro-5-nitroaniline (861 mg; 5.52 mmol; 1.02eq); Im₂CS (960.3 mg; 5.39 mmol) and dry K₂CO₃ (1.45g) was suspended indry DME (10 mL) and stirred under nitrogen for 90 min at roomtemperature. The yellow suspension was made fluid by diluting with DME(10 mL) followed by addition of 40% MeNH₂ in water (4.0 mL; 46.5 mmol;8.6 eq). The system was heated up to 65 C. and stirred at thistemperature for 3.5 h, cooled down, diluted with ethyl acetate andwashed with saturated NaCl (×2). After conventional work-up procedures,the dark crude mixture was purified through chromatographic column onsilica gel (elution 50% EtOAc in hexane, then 5% MeOH in DCM), to afford836.8 mg (4.0 mmol; 72% yield) of compound 456a.

[0709] Step 2: N-Methyl-benzothiazole-2,5-diamine (456b)

[0710] A mixture of nitro compound 456a (593 mg; 2.83 mmol); SnCl₂ (4.02g; 20.8 mmol; 7.35 eq) and NH₄OAc (4.5g) was suspended inTHF:MeOH:H₂O=1:1:1 (60 mL) and stirred at 70° C. for 2 h, cooled down,diluted with ethyl acetate and successively washed with saturated NaHCO₃and brine; dried (MgSO₄) filtered and concentrated. The residue (443 mg;2.43 mmol; 87%) showed consistent spectrum and suitable purity degreefor synthetic purposes, therefore was submitted to the next step withoutfurther purification.

[0711] Step 3: 4-[(2-Methylaminobenzothiazol-5-Ylamino)-Methyl]-BenzoicAcid (456c)

[0712] A solution of aniline 456b (509 mg; 2.8 mmol); 4-formylbenzoicacid (426 mg; 2.8 mmol) and Bu₂SnCl₂ (198 mg; 0.65 mmol; 23% mol) in DME(14 mL) was stirred at room temperature for 3 min and treated with neatPhSiH₃ (0.6 mL; 4.7 mmol; 1.7 mmol) and allowed to react for 18 h. Afterquenching the excess of silane with MeOH, the mixture was concentratedand purified by chromatographic column on silica gel (elution 5% MeOH inDCM) to give 729 mg (2.54 mmol; 91% yield) of acid 456c.

[0713] Step 4:N-(2-Aminophenyl)-4-[(2-methylaminobenzothiazol-5-ylamino)-methyl]-benzamide(456)

[0714] A mixture of acid 456c (729 mg; 2.54 mmol), 1,2-phenylenediamine(376 mg; 3.47 mmol; 1.36 eq) and BOP (1.43 g; 3.23 mmol; 1.27 eq) wasdissolved in acetonitrile (15 mL), treated with triethylamine (3mL) andstirred overnight. The reaction mixture was quenched with methanol,concentrated and purified by chromatographic column on silica gel (40%EtOAc in DCM) and the obtained material crystallized from DCM to give358 mg (0.88 mmol; 35% yield) of pure compound 456. ¹H-NMR (300 MHz;DMSO-d6) δ(ppm): 9.57 (s, 1H), 7.92 (d, J=7.9 Hz, 2H), 7.66 (d, J=4.8Hz, 1H), 7.48 (d, J=8.3 Hz, 2H), 7.26 (d, J=8.3 Hz, 1H), 7.15 (d, J=7.9Hz, 1H), 6.95 (t, J=7.5 Hz, 1H), 6.76 4.87 (bs, 2H), 6.58 (t, J=7.5 Hz,1H), 6.54 (d, J=1.8 Hz, 1H), 6.13 (dd, J=1.8, 8.3 Hz, 1H), 6.27 (t,J=5.7 Hz, 1H), 4.87 (bs, 2H), 4.36 (d, J=5.7 Hz, 2H), 2.85 (d, J=4.8 Hz,3H). LRMS: calc: 403.5008, found: 404.2 (M+NH) and 202.6 (M+2H)/2.

Example 235

[0715] Step 1:Methyl-4-(5-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoate (376a)

[0716] To a solution 5-methoxy-2-thiobenzimidazole (2.00 g, 11.1 mmol ofin anhydrous DMF (40 ml) was added methy-4-bromomethyl)-benzoate (2.54g, 11.1 mmol). The reaction mixture was stirred 16 h at roomtemperature. The DMF was evaporated and the residue was triturated inethyl acetate during 30 min and then filtered and dried. The desiredcompound was isolated as the HBr salt: 98% yield, (4.44 g). ¹H NMR:(DMSO) δ(ppm): 7.90 (d, J=8.8 Hz, 2H), 7.56-7.52 (m, 3H), 7.09 (d, J=2.2Hz, 1H), 7.01 (dd, J=8.8 , 2.2 Hz, 1H), 4.73 (s, 2H), 3.82 (s, 6H). MS:(calc.) 328.1, (obt.), 329.2 (MH)+.

[0717] Step 2: 4-(5-Methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoicacid (376b)

[0718] A solution of LiOH.H20 (1.02 g, 24.4 mmol) in water (15 ml) wasadded to a suspension of 376a (3.99 g, 9.75 mmol of in THF (10 ml). Thereaction mixture was stirred 16 h at room temperature. The reactionmixture was acidified with a solution of HCl 1 M to pH 4. The desiredproduct was triturated 20 min. at 0° C. and then filtered and dried.Compound 376b was obtained as a white powder (100% yield, 3.05 g). ¹HNMR: (DMSO) δ(ppm): 12.85 (bs, 1H), 7.86 (d, J=8.1 Hz, 2H), 7.53 (d,J=8.1 Hz, 2H), 7.35 (d, J=8.1 Hz, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.76 (dd,J=8.8 , 2.2 Hz, 1H), 4.60 (s, 2H), 3.82 (s, 3H). MS: (calc.) 314.1,(obt.), 315.1 (MH)+.

[0719] Step 3:N-(2-Amino-phenyl)-4-5-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzamide(376)

[0720] Following the procedure described in Example 1 step 5 butsubstituting 445-methoxy-1H-benzimidazol-2-yl-sulfanylmethyl)-benzoicacid 2 for 7 the title compound 376 was obtained as a white powder.: 36%yield (933 mg). ¹H NMR: (DMSO) δ(ppm): 12.42 (bs, 1H), 9.57 (bs, 1H),7.89 (d, J=8.1 Hz, 2H), 7.55 (d, J=8.1 Hz, 2H), 7.34 (d, J=8.8 Hz, 1H),7.14 (d, J=7.32 Hz, 1H), 6.98-6.93 (m, 2H), 6.77-6.55 (m, 2H), 6.58 (dd,J=7.3, 7.3 Hz, 1H), 4.87 (s, 2H), 3.77 (s, 3H). MS: (calc.) 404.1,(obt.), 405.4 (MH)+.

Examples 180-328

[0721] Examples 180 to 327 (compounds 320-468) were prepared using thesame procedure as described for compound 126 to 319 in Example 85 to 179(scheme 11 to 58).

Examples 329-344

[0722] Examples 329 to 344 (compounds 470-485) were prepared using thesame procedure as described for compound 8 to 224 in Example 1 to 143(scheme 1 to 32).

Example 345

[0723] Step 1: Methyl 3-(4-bromo-phenyl)-acrylic ester (486)

[0724] To a solution of anhydrous i-Pr₂NH (758 μl, 5.40 mmol) inanhydrous THF (25 ml) stirred at 0° C. under nitrogen , was slowly addeda solution of n-BuLi (2.22 ml, 5.54 mmol, 2.5 M in hexane). After 30min, LDA was cooled to −78° C. and anhydrous methyl acetate (430

1, 5.40 mmol) was added dropewise. After 30 min, a solution of4-bromobenzaldehyde (500 mg, 2.70 mmol) in anhydrous THF (10 ml) wasslowly added. After 30 min, a solution of2-chloro-4,6-dimethoxy-1,3,5-triazine (569 mg, 3.24 mmol) in anhydrousTHF (15 ml) was added. Then, the temperature was allowed to warm up toroom temperature overnight. A suspension appeared. The reaction mixturewas poured into a saturated aqueous solution of NH₄Cl, and diluted withAcOEt. After separation, the organic layer was successively washed withH₂O and brine, dried over MgSO₄, filtered and concentrated. The crudeproduct was purified by flash chromatography on silica gel(AcOEt/hexane: 10/90) to give the title product 486 (394 mg, 1.9 mmol,61% yield) as a colorless crystalline solid. ¹H NMR (300 MHz, CDCl₃)δ(ppm): 7.63 (d, J=16.2 Hz, 1H), AB system (δ_(A)=7.53, δ_(B)=7.39,J=8.4 Hz, 4H), 6.43 (d, J=15.8 Hz, 1H), 3.82 (s, 3H).

[0725] Step 2: Methyl3-[4-(3,4,5-trimethoxy-phenylamino)-phenyl]-acrylic ester (487)

[0726] A mixture of Cs₂CO₃ (378 mg, 1.16 mmol), Pd(OAc)₂ (6 mg, 0.025mmol), (rac)-BINAP (23 mg, 0.037 mmol), was purged with nitrogen for 10min. 486 (200 mg, 0.83 mmol), 3,4,5-trimethoxyaniline (182 mg, 0.99mmol), and anhydrous toluene (5 ml) were added, respectively. Thereaction mixture was heated to 100° C. under nitrogen for 24 h. Then, itwas allowed to cool to room temperature, diluted with AcOEt, andsuccessively washed with a saturated aqueous solution NaHCO₃, H₂O, sat.NH₄Cl, H₂O and brine, dried over anhydrous MgSO₄, filtered andconcentrated. The crude residue was then purified by flashchromatography on silica gel (AcOEt/hexane: 40/60) to afford the titlecompound 487 (280 mg, 0.82 mmol, 98% yield) as a yellow oil. ¹H NMR (300MHz, CDCl₃) δ(ppm): 7.64 (d, J=16.2 Hz, 1H), 7.43 (bd, J=7.9 Hz, 2H),7.12-6.86 (m, 2H), 6.60-6.20 (m, 3H, included at 6.29, d, J=15.8 Hz),3.84 (s, 9H), 3.80 (s, 3H). Step 3:N-(2-Amino-phenyl)-3-[4-(3,4,5-trimethoxy-phenylamino)-phenyl]-acrylamide(488)

[0727] The title compound 488 was obtained from 487 in 2 steps followingthe same procedure as Example 1, steps 4 and 5. ¹H NMR (300 MHz,DMSO-d₆) δ(ppm): 9.29 (s, 1H), 8.48 (s, 1H), 7.60-7.42 (m, 3H), 7.38 (d,J=7.5 Hz, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.94 (t, J=7.5 Hz, 1H), 6.78 (d,J=7.9 Hz, 1H), 6.71 (d, J=15.8 Hz, 1H), 6.61 (t, J=7.1 Hz, 1H), 6.47 (s,2H), 4.97 (s, 2H), 3.79 (s, 6H), 3.66 (s, 3H).

Example 346

[0728] Step 1: 3-(4-Formyl-3-methoxy-phenyl)-acrylic acid tert-butylester 489

[0729] Following the procedure described in Example 53, step 1, butsubstituting 4-hydroxy-2-methoxy-benzaldehyde for 84, followed byExample 42, step 2, but substituting the previous compound for 42, thetitle compound 489 was obtained in 29% yield. LRMS=calc: 262, found:263.2 (M+H⁺).

[0730] Step 2:3-{3-Methoxy-4-[(3,4,5-trimethoxy-phenylamino)-methyl]-phenyl}-acrylicacid tert-butyl ester

[0731] Following the procedure described in Example 144, step 3, butsubstituting 489 for 4-formylbenzaldehyde, the title compound 490 wasobtained in 69% yield. LRMS=calc: 429, found: 430.5 (M+H⁺).

[0732] Step 3:N-(2-Amino-phenyl)-3-{3-methoxy-4-[(3,4,5-trimethoxy-phenylamino)-methyl]-phenyl}-acrylamide

[0733] Following the procedure described in Example 42, step 3, 4, butsubstituting 490 for 46, the title compound 491 was obtained in 67%yield. ¹H NMR (CDCl₃), δ(ppm): 8.08 (s, 1H), 7.74 (d, J=15.4 Hz, 1H),7.30 (m, 1H), 7.06 (m, 3H); 6.80 (m, 3H), 6.70 (d, J=15.4 Hz, 1H), 5.98(s, 2H), 4.40 (s, 2H); 4.12 (bs, 3H), 3.94 (s, 3H), 3.84 (s, 3H), 3.77(s, 6H).

Example 436

[0734] Step 1: Methyl-5-methyl-benzofuran-2-carboxylate (583)

[0735] A stirring suspension of 5-methylsalicylaldehyde (1.0 mg, 7.5mmol), K₂CO₃(1.55 g, 11.0 mmol), and Bu₄NBr (322 mg, 1 mmol) in toluene(30 ml) was treated with dimethylbromomalo-nate (1.06 ml, 8.0 mmol). Thesuspension was heated to reflux with a Dean-Stark trap for 20 h. Thebrown suspension was cooled to 25° C. and concentrated in vacuo. Theresidue was taken in DCM and filtered. The filtrate was washed with H₂O,1N NaOH and brine. The organic layer was dried over magnesium sulfate,filtered and concentrated. The crude residue was purified by columnchromatography (10% ethyl acetate/hexane) to afford the title compound583 (600 mg, 42% yield). LRMS: 190.2 (Calc.); 191.1 (found).

[0736] Step 2: Methyl-5-bromomethyl-benzofuran-2-carboxylate (585)

[0737] A mixture of 583 (500 mg, 2.63 mmol), N-bromosuccinimide (561 mg,3.15 mmol) and 1,1′-azobis(cyclohexanecarbonitrile) (Vazo) (63 mg, 0.26mmol) in 15 ml of CCl₄ was heated overnight under reflux. The mixturewas cooled to room temperature, quenched by adding water and extractedwith DCM. The organic layer was washed with brine and dried over MgSO₄,filtered and concentrated. The crude residue was purified by columnchromatography (30% ethyl acetate/hexane) to afford the title compound585 (680 mg, 96% yield). ¹H NMR: (CDCl₃) δ(ppm): 7.79 (s, 1H), 7.70-7.52(m, 3H), 4.69 (s, 2H), 4.06 (s, 3H), 3.72 (s, 2H). LRMS: 268.2 (Calc.);269.1 (found).

[0738] Step 3:Methyl-5-[(3,4-dimethoxy-phenylamino)-methyl]-benzofuran-2-carboxylate(586)

[0739] Following the procedure described in Example 47, step 2, butsubstituting 585 for 63, the title compound 586 was obtained in 40%yield. LRMS: 341 (Calc.); 342.3 (found).

[0740] Step 4:5-[(3,4-Dimethoxy-phenylamino)-methyl]-benzofuran-2-carboxylic acid(2-amino-phenyl)-amide (587)

[0741] Following the procedure described in Example 1, steps 4,5, butsubstituting 585 for 6, the title compound 587 was obtained in 29%yield. ¹H NMR: (DMSO) δ(ppm): 9.83 (s, 1H), 7.75 (s, 1H), 7.64 (s, 1H),7.62 (d, J=8.0 Hz, 1H), 7.47 (d, J=9.0 Hz, 1H), 7.18 (d, J=8.0 Hz, 1H),6.97 (t, J=7.5 Hz, 1H), 6.78 (d, J=8.0 Hz, 1H), 6.65 (d, J=8.5 Hz, 1H),6.59 (t, J=7.5 Hz, 1H), 6.33 (s, 1H), 6.04 (d, J=8.0 Hz, 1H), 5.92 (d,J=5.5 Hz, 1H), 4.93 (s, 2H), 4.31 (d, J=5.5 Hz, 1H), 2.82 (s, 3H), 2.76(s, 3H). LRMS: 417.46 (Calc.); 418.4 (found).

Example 437

[0742] Step 1: Methyl-5-nitro-benzo[b]thiophene-2-carboxylate (584)

[0743] A stirring suspension of 5-nitro-2-chloro-benzaldehyde (4.0 g,21.6 mmol) in DMF (40 ml) at 5° C. was treated with K₂CO₃(3.52 g, 25.5mmol) followed by methylglycolate (1.93 ml, 21.6 mmol). The resultingsolution was warmed to 25° C. and stirred for 20 h. The solution wasthen poured into 250 ml of ice H₂O and the white precipitate that formedwas collected by filtration. Crystallization from EtOAc afforded finepale orange needles of 584 (3.54 g, 69%). LRMS: 237.0 (Calc.); 238.1(found). ¹H NMR: (DMSO) δ(ppm): 9.00 (d, J=2.2 Hz, 1H), 8.45 (s, 1H),8.39-8.30 (m, 2H), 3.93 (s, 3H).

[0744] Step 2: Methyl-5-amino-benzo[b]thiophene-2-carboxylate (588)

[0745] A suspension of 584 (3.52 g, 14.8 mmol) in methanol (100 ml) wastreated with Fe powder (6.63 g, 118.7 mmol). The resulting suspensionwas heated to reflux, and 12M HCl (8.5 ml) was slowly added over 15 min.The resulting green dark suspension was refluxed for an additional 3 h,then cooled and concentrated. The residue was taken up in EtOAc andwashed with saturated aqueous NaHCO₃, then brine, dried over MgSO₄,filtered and concentrated to afford (2.57 g, 84%). ¹H NMR: (DMSO)δ(ppm): 7.92 (s, 1H), 7.65 (d, J=8.8 Hz, 1H), 7.05 (d, J=1.5 Hz, 1H),6.88 (dd, J=1.8, 8.4 Hz, 1H), 5.27 (s, 2H), 3.85 (s, 3H). LRMS: 207.0(Calc.); 208.1 (found).

[0746] Step 3:Methyl-5-(3,4,5-trimethoxy-benzylamino)-benzo[b]thiophene-2-carboxylate(589)

[0747] Following the procedure described in Example 144, step 3, butsubstituting 588 for 226, the title compound 589 was obtained in 68%yield. (DMSO) δ(ppm): 7.94 (s, 1H), 7.69 (d, J=8.8 Hz, 1H), 7.02-6.99(m, 2H), 6.73 (s, 2H), 6.41 (t, J=5.7 Hz, 1H), 4.21 (d, J=5.9 Hz, 2H),3.84 (s, 3H), 3.75 (s, 6H), 3.62 (s, 3H). LRMS: 387.1 (Calc.); 388.3(found).

[0748] Step 4:5-(3,4,5-Trimethoxy-benzylamino)-benzo[b]thiophene-2-carboxylic acid(2-amino-phenyl)-amide (590)

[0749] Following the procedure described in Example 1, steps 4,5, butsubstituting 589 for 6, the title compound 590 was obtained in % yield¹HNMR: (DMSO) δ(ppm): 7.79 (s, 1H), 7.60 (d, J=8.8 Hz, 1H), 7.00-6.95 (m,2H), 6.74 (s, 2H), 4.32 (s, 2H), 3.80 (s, 6H), 3.73 (s, 3H).

Examples 347-425

[0750] Examples 347 to 425 (compounds 492-570) were prepared using thesame procedure as described for compound 44 to 491 in Example 40 to 346(scheme 3 to 64).

Assay Example 1 Inhibition of Histone Deacetylase Enzymatic Activity

[0751] 1. Human HDAC-1

[0752] HDAC inhibitors were screened against a cloned recombinant humanHDAC-1 enzyme expressed and purified from a Baculovirus insect cellexpression system. For deacetylase assays, 20,000 cpm of the[³H]-metabolically labeled acetylated histone substrate (M. Yoshida etal., J. Biol. Chem. 265(28): 17174-17179 (1990)) was incubated with 30μg of the cloned recombinant hHDAC-1 for 10 minutes at 37° C. Thereaction was stopped by adding acetic acid (0.04 M, final concentration)and HCl (250 mM, final concentration). The mixture was extracted withethyl acetate and the released [³H]-acetic acid was quantified byscintillation counting. For inhibition studies, the enzyme waspreincubated with compounds at 4° C. for 30 minutes prior to initiationof the enzymatic assay. IC₅₀ values for HDAC enzyme inhibitors weredetermined by performing dose response curves with individual compoundsand determining the concentration of inhibitor producing fifty percentof the maximal inhibition. IC₅₀ values for representative compounds arepresented in the third column of Table 5.

[0753] 2. MTT Assay

[0754] HCT116 cells (2000/well) were plated into 96-well tissue cultureplates one day before compound treatment. Compounds at variousconcentrations were added to the cells. The cells were incubated for 72hours at 37° C. in 5% CO₂ incubator. MTT(3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide, Sigma)was added at a final concentration of 0.5 mg/ml and incubated with thecells for 4 hours before one volume of solubilization buffer (50%N,N-dimethylformamide, 20% SDS, pH 4.7) was added onto the culturedcells. After overnight incubation, solubilized dye was quantified bycalorimetric reading at 570 nM using a reference at 630 nM using anMR700 plate reader (Dynatech Laboratories Inc.). OD values wereconverted to cell numbers according to a standard growth curve of therelevant cell line. The concentration which reduces cell numbers to 50%of that of solvent treated cells is determined as MTT IC₅₀. IC₅₀ valuesfor representative compounds are presented in the fourth column of Table5.

[0755] 3. Histone H4 Acetylation in Whole Cells by Immunoblots

[0756] T24 human bladder cancer cells growing in culture were incubatedwith HDAC inhibitors for 16 h. Histones were extracted from the cellsafter the culture period as described by M. Yoshida et al. (J. Biol.Chem. 265(28): 17174-17179 (1990)). 20 g of total histone protein wasloaded onto SDS/PAGE and transferred to nitrocellulose membranes.Membranes were probed with polyclonal antibodies specific for acetylatedhistone H-4 (Upstate Biotech Inc.), followed by horse radish peroxidaseconjugated secondary antibodies (Sigma). Enhanced Chemiluminescence(ECL) (Amersham) detection was performed using Kodak films (EastmanKodak). Acetylated H-4 signal was quantified by densitometry.Representative data are presented in the fifth column of Table 5. Dataare presented as the concentration effective for reducing the acetylatedH-4 signal by 50% (EC₅₀). TABLE 5a Inhibition of Histone DeacetylaseHuman MTT H4Ac HDAC-1 (HCT116) (T24) Cpd Structure IC₅₀(μM) IC₅₀(μM)EC₅₀(μM)  8

0.4 0.5 1  9

2 0.7 5 10

2 0.6 1 11

2 0.6 2 12

2 2 5 14

0.3 1 5 15

0.5 0.2 3 16

1 0.4 1 17

0.9 1 2 18

0.8 0.6 3 18b

0.6 5 10 19

0.9 1 1 20

0.5 0.3 1 21

4 4 25 22

3 0.8 1 23

2 0.7 1 24

3 0.6 1 25

0.8 0.3 5 26

0.5 2 na 27

0.4 2 na 28

2 0.5 1 29

2 2 1 30

1 3 1 83

3 5 5

[0757] TABLE 5b

Human MTT HDAC-1 (HCT116) H4Ac(T24) Ex Cpd Structure IC₅₀(μM) IC₅₀(μM)EC₅₀(μM) 135 204

4 na 5 136 207

0.4 0.6 2 137 210

3 0.9 1 138 212

3 1 1 139 214

3 0.9 1 140 216

0.5 0.4 2 141 218

0.1 0.5 na 142 220

7 6 na 143a 223

11 2 na 143b 224

5 3 na 329 470

2 0.7 3 330 471

0.4 1 3 331 472

3 1 1 332 473

4 3 na 333 474

3 1 1 334 475

0.6 2 na 335 476

2 1 2 336 477

1 0.7 na 337 478

3 0.7 na 338 479

0.4 0.6 na 339 480

0.8 0.5 na 340 481

6 0.7 na 341 482

0.1 0.7 na 342 483

4 na na 343 484

2 0.3 na 344 485

0.4 3 na

[0758] TABLE 5c HumanHDAC-1 MTT(HCT116) H4Ac(T24) Cpd Structure IC₅₀(μM)IC₅₀(μM) EC₅₀(μM) 51

22 4 na 55b

3 8 3 59

12 22 na 61b

7 12 na 65

4 37 na 71

10 44 na 72

16 21 na 88

na >39 na 90

10 5 5 91

4 7 5 92

5 2 3 93

3 1 5 94

3 2 5 95

3 2 10 96

4 3 25 97

10 12 na 98

0.4 2 15 99

2 5 10 100

4 3 5 101

3 0.9 5 102

20 6 na 104

10 9 5 105

16 14 na 106

2 2 1 107

15 17 na 108

3 5 5 109

5 8 15 110

3 999 na 111

10 2 99 112

2 5 5 113

0.3 5 114

25 0.5 99 115

15 9 na 116

4 2 5 117

7 3 na 118

11 8 na

[0759] TABLE 5d HDAC-1 MTT(HCT116) H4Ac(T24) Ex. Cpd Structure IC50(μM)IC50(μM) EC50(μM) 338 481

22 10 — 339 484

20 12 — 347 492

4 9 10 348 493

4 5 — 349 494

3 4 — 350 495

4 7 — 351 496

8 13 — 352 497

15 6 — 353 498

>25 — — 354 499

>25 2 >25 355 500

23 37 — 356 501

4 10 — 357 502

3 >25 — 358 503

5 >25 — 359 504

5 >25 — 360 505

3 6 — 361 506

15 11 — 362 507

17 10 — 363 508

22 11 — 364 509

17 11 — 365 510

6 5 — 366 511

4 >25 — 367 512

3 3 5 371 516

15 15 — 372 517

6 5 — 373 518

4 2 5 374 519

99 6 — 375 520

5 3 — 376 521

5 2 10 377 522

17 30 — 378 523

8 6 10 379 524

3 2 3 380 525

3 4 5 381 526

2 0.8 1 382 527

4 3 — 383 528

20 32 — 384 529

5 17 — 385 530

8 9 — 386 531

3 2 20 387 532

3 5 — 388 533

5 11 — 389 534

3 5 — 390 535

4 6 — 391 536

18 9 — 392 537

11 2 >25 393 538

4 12 — 394 539

2 10 — 395 540

10 10 — 396 541

4 12 — 397 542

2 5 4 398 543

15 >25 — 399 544

17 45 — 400 545

2 12 — 401 546

3 10 — 402 547

4 8 — 403 548

3 9 — 404 549

4 19 — 405 550

4 15 — 406 551

24 9 — 407 552

4 22 — 408 553

4 12 — 409 554

15 12 — 410 555

14 7 — 411 556

1 0.4 15 412 557

4 6 — 413 558

7 10 — 414 559

4 11 — 415 560

21 6 — 416 561

>25 >25 — 417 562

5 5 — 418 563

24 6 — 419 564

>25 >25 — 420 565

5 17 — 421 566

3 16 — 422 567

13 3 — 423 568

>25 39 — 424 569

18 6 — 425 570

6 0.6 2

[0760] TABLE 5e Human HDAC-1 MTT(HCT116) H4Ac(T24) Cpd StructureIC₅₀(μM) IC₅₀(μM) EC₅₀(μM) 87

2 1 5 126

0.3 0.2 1 128

1 0.3 5 131

0.3 0.9 2 139

3 3 5 141

7 10 na 149

1 5 5 152

0.3 11 na 154

0.3 0.4 >1 155

0.4 0.4 1 157

2 0.6 1 158

0.4 0.2 1 164

3 2 3 165

9 4 25 166

2 5 5 167

4 0.5 2 168

3 0.8 2 169

0.3 0.7 1 171

8 3 25 172

0.4 1 3 174

4 0.4 5 175

4 0.5 3 176

5 1 3 177

1 0.4 1

[0761] TABLE 5f Human MTT HDAC-1 (HCT116) H4 Ac(T24) Ex Cpd StructureIC₅₀(μM) IC₅₀(μM) EC₅₀(μM) 117 179

1 0.3 1 118 180

3 2 5 119 181

0.5 0.4 1 122 186

2 2 2 123 187

2 5 2 125 189

3 2 5 126 190

3 1 >5 127 192

2 1 3 128 193

4 16 129 194

3 11 130 195

7 9 131 196

4 3 132 198

24 14 133 199

7 9 134 201

11 5 144 228

3 0.3 1 145 231

4 1 3 146 233

0.9 0.3 1 147 236

5 6 148 238

3 6 149 240

1.8 10 150 243

2 0.8 1 151 247

3 0.6 2 152 249

4 1 2 153 252

8 1 2 154 255

2 0.8 1 155 257

0.4 0.4 1 156 259

3 0.3 1 157 262

0.5 0.3 1 158 265

2 2 3 159 266

0.4 0.9 2 160 269

9 4 161 270

4 1 5 162 272

2 0.6 <1 163 275

4 0.9 2 164 277

4 0.3 1 165 281

0.5 0.6 1 166 284

3 5 167 286

5 2 168 289

17 5 169 290

11 3 170 296

20 7 171 297

7 0.4 1 172 301

3 3 173 305

4 2 174 311

0.9 0.7 1 178 317

2 0.3 1 179 319

4 8 180 320

2 1 181 321

0.5 0.3 5 182 322

0.7 0.4 2 183 323

1 0.6 1 184 325

0.3 1 2 185 326

1 1 3 186 327

2 5 3 187 328

17 10 189 330

3 2 1 190 331

4 10 191 332

0.4 1 5 192 333

2 0.1 1 193 334

8 0.2 1 195 336

1 0.4 <1 196 337

3 0.6 1 197 338

2 0.5 3 198 339

4 3 199 340

2 1 1 200 341

4 1 3 201 342

3 0.4 1 202 343

0.5 0.3 1 203 344

0.5 0.2 1 204 345

0.4 0.8 1 205 346

3 0.5 <1 206 347

2 0.6 2 207 348

2 0.3 1 208 349

13 1 3 209 350

2 1 5 211 352

16 9 212 353

3 10 213 354

15 5 214 355

25 10 215 356

5 2 216 357

4 0.4 2 217 358

3 1 2 218 359

2 0.3 1 219 360

5 0.2 1 220 361

2 0.5 1 221 362

2 0.7 1 222 363

1 0.3 3 223 364

4 0.6 224 365

3 0.6 3 225 366

14 10 226 367

6 2 5 230 371

4 0.5 2 231 372

2 0.2 1 232 373

4 0.4 1 233 374

2.5 0.3 1 234 375

3 4 25 235 376

3 0.1 1 236 377

4 2 3 237 378

2 0.7 2 238 379

2 0.6 15 239 380

6 8 240 381

2 1 2 241 382

3 1 3 242 383

2 0.5 2 243 384

3 2 5 244 385

3 1 2 245 386

3 1 1 246 387

2 1 1 247 388

3 0.4 5 248 389

3 0.2 1 249 390

2 0.8 5 250 391

1 0.9 3 251 392

4 1 1 252 393

4 0.6 1 253 394

4 2 25 254 395

2 1 5 255 396

2 0.7 5 256 397

1 0.6 4 258 399

14 9 259 400

8 0.3 2 260 401

6 0.3 2 261 402

14 0.4 1 262 403

1 0.2 1 263 404

3 0.6 5 264 405

5 1 5 265 406

3 11 266 407

3 2 267 408

4 2 268 409

3 1 9999 269 410

0.9 0.1 >5 270 411

2 1 271 412

3 2 3 272 413

2 2 3 273 414

3 1 1 274 415

3 1 3 275 416

3 0.6 1 276 417

3 1 1 277 418

3 0.9 2 278 419

2 1 5 279 420

3 0.7 1 280 421

4 0.6 1 281 422

<0.05 0.9 5 282 423

0.5 1 3 283a 424b

2 0.4 1 283b 424c

3 0.8 3 284 425

2 0.6 5 285 426

2 1 10 286 427

0.6 2 1 287 428

0.7 0.7 1 288 429

4 0.9 1 289 430

5 0.7 1 290 431

5 5 291 432

2 1 3 292 432

2 0.6 1 293 434

4 0.6 2 294 435

3 0.6 1 295 436

5 0.8 5 296 437

3 0.4 1 297 438

5 0.6 1 298 439

3 0.4 1 299 440

4 0.1 2 300 441

2 0.8 2 301 442

17 0.4 1 302 443

303 444

304 445

16 6 305 446

21 7 307 448

3 0.2 2 308 449

1 6 309 450

3 2 310 451

4 0.2 3 311 452

3 0.3 2 312 453

9999 37 313 454

4 2 5 314 455

4 0.7 1 315 456

3 0.4 8888 316 457

9999 9999 317 458

3 0.3 2 318 459

4 0.3 1 319 460

3 1 1 320 461

1.4 0.3 1 321 462

4 0.3 1 322 463

12 6 323 464

4 11 324 465

2 9999 9999 325 466

3 2 1 326 467

4 0.4 2 327 468

2 8 <1 426 571

4 11 427 572

1.5 5 5 428 573

7 0.4 1 429 574

13 0.7 3 430 575

2 0.2 1 431 576

5 6 432 577

2 0.5 2 433 578

0.6 0.1 1 434 579

2 0.5 1 435 580

4 0.3 <1 436 587

5 0.8 2 437 590

2 2 3 438 591

4 0.3 <1 439 592

5 0.4 <1

Assay Example 2 Antineoplastic Effects of Histone Deacetylase InhibitorSon Human Tumor Xenografts In Vivo

[0762] Eight to ten week old female BALB/c nude mice (Taconic Labs,Great Barrington, N.Y.) were injected subcutaneously in the flank areawith 2×10⁶ preconditioned HCT116 human colorectal carcionoma cells.Preconditioning of these cells was done by a minimum of threeconsecutive tumor transplantations in the same train of nude mice.Subsequently, tumor fragments of approximately 30 mgs were excised andimplanted subcutaneously in mice, in the left flank area, under Foreneanesthesia (Abbott Labs, Geneve, Switzerland). When the tumors reached amean volume of 100 mm³, the mice were treated intravenously,subcutaneously, or intraperitoneally by daily injection, with a solutionof the histone deacetylase inhibitor in an appropriate vehicle, such asPBS, DMSO/water, or Tween 80/water, at a starting dose of 10 mg/kg. Theoptimal dose of the HDAC inhibitor was established by dose responseexperiments according to standard protocols. Tumor volume was calculatedevery second day post infusion according to standard methods (e.g.,Meyer et al., Int. J. Cancer 43:851-856 (1989). Treatment with the HDACinhibitors according to the invention caused a significant reduction intumor weight and volume relative to controls treated with vehicle only(i.e., no HDAC inhibitor). In addition, the level of histone acetylationwhen measured was significantly elevated relative to controls. Data forselected compounds are presented in Table 6. FIG. 1 shows the fullexperimental results for compound 106, which inhibits tumor growth by80%. FIGS. 2-10 show the results of additional compounds tested. TABLE 6Antitumor Activity in HCT 116 Colorectal Tumor Model In Vivo Compound %Inhibition of Tumor Growth 106 80^(a) 126 62^(b) 9 51^(b) 87 30^(b) 15766^(a) 167 58^(a) 15 26^(b) 168 26^(b) 16 50^(b) 154 23^(a) 98 52^(a)

[0763] TABLE 7 Antineoplastic Effects Of Histone Deacetylase InhibitorsOn Nude Mice Xenograft Models % Inhibition Of Tumor Growth cpd A 549(p.o.) SW48 (p.o.) A 549 (i.p.) HCT 116 (i.p.) SW 48 (i.p.) 106 40% (70mg/kg) 16% (60 mg/kg) — — — 164 42% (70 mg/kg) 62% (60 mg/kg) — 37% (20mg/kg) 99% (25 mg/kg) 228 45% (70 mg/kg) 25% (60 mg/kg) 64% (20 mg/kg)45% (20 mg/kg) 68% (20 mg/kg)  424b 67% (50 mg/kg) 78% (30 mg/kg) 60%(50 mg/kg) 77% (75 mg/kg) 68% (25 mg/kg)

Assay Example 3 Combined Antineoplastic Effect of Histone DeacetylaseInhibitors and Histone Deacetylase Antisense Oligonucleotides on TumorCells In Vivo

[0764] The purpose of this example is to illustrate the ability of thecombined use of a histone deacetylase inhibitor of the invention and ahistone deacetylase antisense oligonucleotide to enhance inhibition oftumor growth in a mammal. Preferably, the antisense oligonucleotide andthe HDAC inhibitor inhibit the expression and activity of the samehistone deacetylase.

[0765] As described in Example 126, mice bearing implanted HCT116 tumors(mean volume 100 mm³) are treated daily with saline preparationscontaining from about 0.1 mg to about 30 mg per kg body weight ofhistone deacetylase antisense oligonucleotide. A second group of mice istreated daily with pharmaceutically acceptable preparations containingfrom about 0.01 mg to about 5 mg per kg body weight of HDAC inhibitor.

[0766] Some mice receive both the antisense oligonucleotide and the HDACinhibitor. Of these mice, one group may receive the antisenseoligonucleotide and the HDAC inhibitor simultaneously intravenously viathe tail vein. Another group may receive the antisense oligonucleotidevia the tail vein, and the HDAC inhibitor subcutaneously. Yet anothergroup may receive both the antisense oligonucleotide and the HDACinhibitor subcutaneously. Control groups of mice are similarlyestablished which receive no treatment (e.g., saline only), a mismatchantisense oligonucleotide only, a control compound that does not inhibithistone deacetylase activity, and a mismatch antisense oligonucleotidewith a control compound.

[0767] Tumor volume is measured with calipers. Treatment with theantisense oligonucleotide plus the histone deacetylase protein inhibitoraccording to the invention causes a significant reduction in tumorweight and volume relative to controls.

We claim:
 1. A histone deacetylase inhibitor of formula (1):

or a pharmaceutically acceptable salt thereof, wherein R³ and R⁴ areindependently selected from the group consisting of hydrogen, L¹, Cy¹,and —L¹—Cy¹, wherein L¹ is C₁-C₆ alkyl, C₂-C₆ heteroalkyl, orC₃-C₆alkenyl; and Cy¹ is cycloalkyl, aryl, heteroaryl, or heterocyclyl,each of which is optionally substituted, and each of which is optionallyfused to one or two aryl or heteroaryl rings, or to one or two saturatedor partially unsaturated cycloalkyl or heterocyclic rings, each of whichrings is optionally substituted; or R³ and R⁴ are taken together withthe adjacent nitrogen atom to form a 5-, 6-, or 7-membered ring, whereinthe ring atoms are independently selected from the group consisting ofC, O, S, and N, and wherein the ring is optionally substituted, andoptionally forms part of a bicyclic ring system, or is optionally fusedto one or two aryl or heteroaryl rings, or to one or two saturated orpartially unsaturated cycloalkyl or heterocyclic rings, each of whichrings and ring systems is optionally substituted; Y¹ is selected fromthe group consisting of —N(R¹)(R²), —CH₂—C(O)—N(R¹)(R²), halogen, andhydrogen, wherein R¹ and R² are independently selected from the groupconsisting of hydrogen, L¹, Cy¹, and —L¹—Cy¹, wherein L¹ is C₁-C₆ alkyl,C₂-C₆ heteroalkyl, or C₃-C₆ alkenyl; and Cy¹ is cycloalkyl, aryl,heteroaryl, or heterocyclyl, each of which is optionally substituted,and each of which is optionally fused to one or two aryl or heteroarylrings, or to one or two saturated or partially unsaturated cycloalkyl orheterocyclic rings, each of which rings is optionally substituted; or R¹and R² are taken together with the adjacent nitrogen atom to form a 5-,6-, or 7-membered ring, wherein the ring atoms are independentlyselected from the group consisting of C, O, S, and N, and wherein thering is optionally substituted, and optionally forms part of a bicyclicring system, or is optionally fused to one or two aryl or heteroarylrings, or to one or two saturated or partially unsaturated cycloalkyl orheterocyclic rings, each of which rings and ring systems is optionallysubstituted; Y² is a chemical bond or N(R⁰), where R⁰ is selected fromthe group consisting of hydrogen, alkyl, aryl, aralkyl, and acyl; Ak¹ isC₁-C₆ alkylene, C₁-C₆-heteroalkylene (preferably, in which one —CH₂— isreplaced with —NH—, and more preferably —NH—CH₂—), C₂-C₆ alkenylene orC₂-C₆ alkynylene; Ar¹ is arylene or heteroarylene, either of which isoptionally substituted; and Z¹ is selected from the group consisting of

wherein Ay¹ is aryl or heteroaryl, each of which is optionallysubstituted.
 2. The compound according to claim 1 wherein Ay¹ is phenylor thienyl, each substituted with —OH or —NH₂.
 3. The compound accordingto claim 2 wherein the amino or hydroxy substituent is ortho to thenitrogen to which Ay² is attached.
 4. The compound according to claim 1wherein Ay¹ is ortho aniline, ortho phenol, 3-amino-2-thienyl, or3-hydroxy-2-thienyl.
 5. The compound according to claim 1 wherein Z¹ is


6. The compound according to claim 1 wherein Ar¹ is phenylene.
 7. Thecompound according to claim 1 wherein Ak¹ is alkylene.
 8. The compoundaccording to claim 1 wherein Ak¹ is methylene.
 9. The compound accordingto claim 1 wherein Y² is —NH—.
 10. The compound according to claim 1wherein Y¹ is —N(R¹)(R²) or —CH₂—C(O)—N(R¹)(R²).
 11. The compoundaccording to claim 10 wherein R¹ and/or R² are hydrogen.
 12. Thecompound according to claim 10 wherein R¹ and/or R² are C₁-C₆ alkyl orC₂-C₆ alkenyl.
 13. The compound according to claim 10 wherein R¹ and/orR² are allyl.
 14. The compound according to claim 10 wherein R¹ and/orR² are aryl, heteroaryl, aralkyl, or heteroaralkyl, the rings of each ofwhich optionally are substituted and optionally fused to one or two arylrings.
 15. The compound according to claim 14 wherein R¹ and/or R² areindependently are phenyl, pyridyl, or pyrrolyl.
 16. The compoundaccording to claim 10 wherein R¹ and/or R² are independently cycloalkylwhich is optionally substituted and optionally fused to one or two arylrings
 17. The compound according to claim 16 wherein R¹ and/or R² areindependently cyclopropyl, cyclopentyl, or cyclohexyl, each of which isoptionally substituted and optionally fused to one or two aryl rings.18. The compound according to claim 16 wherein R¹ and/or R² areindependently cyclopropyl, cyclopentyl, or cyclohexyl.
 19. The compoundaccording to claim 1 wherein R³ and/or R⁴ are hydrogen.
 20. The compoundaccording to claim 1 wherein R³ and/or R⁴ are independently C¹-C₆ alkylor C₂-C₆ alkenyl.
 21. The compound according to claim 20 wherein R³and/or R⁴ are allyl.
 22. The compound according to claim 1 wherein R³and/or R⁴ are independently aryl, heteroaryl, aralkyl, or heteroaralkyl,the rings of each of which is optionally substituted and optionallyfused to one or two aryl rings.
 23. The compound according to claim 22wherein R³ and/or R⁴ are independently phenyl, pyridyl, or pyrrolyl. 24.The compound according to claim 1 wherein R³ and/or R⁴ are independentlycycloalkyl.
 25. The compound according to claim 24 wherein R³ and/or R⁴are independently cyclopropyl, cyclopentyl, or cyclohexyl, which isoptionally substituted and optionally fused to one or two aryl rings.26. The compound according to claim 24 wherein R³ and/or R⁴ areindependently cyclopropyl, cyclopentyl, or cyclohexyl.
 27. The compoundaccording to claim 1 wherein L¹ is C₁-C₆ alkyl, C₂-C₆ heteroalkyl, orC₃-C₆ alkenyl.
 28. The compound according to claim 27 wherein L¹ isC₁-C₆ alkylene
 29. The compound according to claim 27 wherein L¹ ismethylene or ethylene.
 30. The compound according to claim 27 wherein L¹is allyl.
 31. The compound according to claim 1 wherein Cy¹ isheterocyclyl that is optionally substituted and optionally fused to oneor two aryl rings
 32. The compound according to claim 31 wherein Cy¹ ispiperidine, pyrrolidine, piperazine, or morpholine, each of which isoptionally substituted and optionally fused to one or two aryl rings.33. The compound according to claim 31 wherein Cy¹ is piperidine,pyrrolidine, piperazine, or morpholine
 34. The compound according toclaim 1 wherein Cy¹ is cycloalkyl.
 35. The compound according to claim34 wherein Cy¹ is cyclopropyl, cyclopentyl, or cyclohexyl.
 36. Thecompound according to claim 1 wherein Cy¹ is aryl or heteroaryl each ofwhich is optionally substituted and is optionally fused to one or twoaryl rings.
 37. The compound according to claim 36 wherein Cy¹ isphenyl, pyridyl, or pyrrolyl, each of which is optionally substitutedand is optionally fused to one or two aryl rings.
 38. The compoundaccording to claim 36 wherein Cy¹ is phenyl, pyridyl, or pyrrolyl. 39.The compound according to claim 36 wherein Cy¹ is fused to one or twobenzene rings.
 40. The compound according to claim 1 wherein Cy¹ hasbetween one and about five substituents independently selected from thegroup consisting of C₁-C₄ alkyl, C₁-C₄ alkoxy, and halo.
 41. Thecompound according to claim 40 wherein the substituents independentlyselected from are methyl, methoxy, and fluoro.
 42. The compoundaccording to claim 1 wherein R¹ and R² together and/or R³ and R⁴together, each with the adjacent nitrogen atom, form a 5- or 6-memberedring, wherein the ring atoms are independently selected from the groupconsisting of C, O, and N, and wherein the ring is optionallysubstituted and is optionally fused to one or two aryl rings.
 43. Thecompound according to claim 42 wherein the 5- or 6-membered ring ispyrrolidine, piperidine, piperazine, or morpholine, and wherein eachring is optionally substituted and optionally fused to an aryl ring. 44.The compound according to claim 43 wherein the aryl ring is benzene. 45.The compound according to claim 43 wherein the substituent comprises anaryl or C₃-C₁₂ cycloalkyl ring, either of which is optionallysubstituted and optionally fused to a C₃-C,₂ cycloalkyl, aryl,heteroaryl, or heterocyclic ring.
 46. The compound according to claim44, wherein the substituent is phenyl, phenylmethyl, or phenylethyl, thephenyl ring of each of which is optionally fused to a C₁-C₁₂ cycloalkyl,aryl, or heterocyclic ring.
 47. A histone deacetylase inhibitor offormula 1(a):

or a pharmaceutically acceptable salt thereof, wherein J isC₁-C₃-hydrocarbyl, —N(R²⁰)—, —N(R²⁰)—CH₂—, —O—, or —O—CH₂—; R²⁰ is —H or—Me; X and Y are independently selected from —NH₂, cycloalkyl,heterocyclyl, aryl, heteroaryl, and A—(C₁-C₆-alkyl)_(n)—B—; A is H,C₁-C₆-alkyloxy, cycloalkyl, heterocyclyl, aryl, or heteroaryl; B is—NH—, —O—, or a direct bond; and n is 0 (in which case A is directlybonded to B) or
 1. 48. The compound according to claim 47 wherein A isphenyl optionally substituted with one or more moieties selected fromhalo and methoxy, and B is —NH—.
 49. The compound according to claim 47wherein A is selected from cyclopropyl, pyridinyl, and indanyl.
 50. Thecompound according to claim 47 wherein J is —NH—CH₂-, —O—CH₂—,—N(CH₃)—CH₂—, —CH═CH—, or —CH₂—CH₂—.
 51. The compound according to claim47 wherein R²⁰ is —H.
 52. The compound according to claim 47 wherein Xis selected from

—OMe,

—NH₂

and

and Y is selected from —NH₂,

n-BuNH, MeOCH₂CH₂NH,

—H Me —OMe CH₃(CH₂)₃NH— and CH₃O(CH₂)₂—NH—.


53. The compound according to claim 47 wherein J, X, and Y are selectedfrom the following combinations: Cpd J X Y 204 —NH—

—NH₂ 207 —OCH₂—

—NH₂ 210 —NHCH₂—

—H 212 —NHCH₂— —OMe —OMe 214 —NHCH₂—

—OMe 216

—Me 218 —NHCH₂—

—Me 220 —CH═CH— —NH₂ —NH₂— 223 —CH═CH—

—NH₂ 224 —CH₂CH₂— —NH₂ —NH₂ 470 —NHCH₂—

NH₂ 471 —NHCH₂—

472 —NHCH₂—

473 —NHCH₂—

n-BuNH 474 —NHCH₂—

MeO(CH2)₂NH 475 —NHCH₂—

476 —NHCH₂—

477 —NHCH₂—

478 —NHCH₂—

479 —NHCH₂—

480 —NHCH₂—

481 —NHCH₂—

482 —NHCH₂—

483 —NHCH₂—

Me 484 —NHCH₂—

NH₂ and 485 —NHCH₂—


54. A histone deacetylase inhibitor of formula (2):

or a pharmaceutically acceptable salt thereof, wherein Cy² iscycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted and each of which is optionally fused to one ortwo aryl or heteroaryl rings, or to one or two saturated or partiallyunsaturated cycloalkyl or heterocyclic rings, each of which rings isoptionally substituted; X¹ is selected from the group consisting of acovalent bond, M¹—L²—M¹, and L²—M²—L² wherein L², at each occurrence, isindependently selected from the group consisting of a chemical bond,C₁-C₄ alkylene, C₂-C₄ alkenylene, and C₂-C₄ alkynylene, provided that L²is not a chemical bond when X¹ is M¹—L²—M¹; M¹, at each occurrence, isindependently selected from the group consisting of —O—, —N(R⁷)—, —S—,—S(O)—, S(O)₂—, —S(O)₂N(R⁷)—, —N(R⁷)—S(O)₂—, —C(O)—, —C(O)—NH—,—NH—C(O)—, —NH—C(O)—O— and —O—C(O)—NH—, wherein R⁷ is selected from thegroup consisting of hydrogen, alkyl, aryl, aralkyl, acyl, heterocyclyl,and heteroaryl; and M² is selected from the group consisting of M¹,heteroarylene, and heterocyclylene, either of which rings is optionallysubstituted; Ar² is arylene or heteroarylene, each of which isoptionally substituted; R⁵ and R⁶ are independently selected from thegroup consisting of hydrogen, alkyl, aryl, and aralkyl; q is 1 or 1; andAy² is a 5-6 membered cycloalkyl, heterocyclyl, or heteroarylsubstituted with an amino or hydroxy moiety (preferably these groups areortho to the amide nitrogen to which Ay² is attached) and furtheroptionally substituted; provided that when Cy² is naphthyl, X¹ is —CH₂—,Ar² is phenyl, R⁵ and R⁶ are H, and q is 0 or 1, Ay² is not phenyl oro-hydroxyphenyl.
 55. The compound according to claim 54 wherein when Ay²is o-phenol optionally substituted by halo, nitro, or methyl, Ar² isoptionally substituted phenyl, X¹ is —O—, —-CH₂—, —S—, —S—CH₂—, —S(O)—,—S(O)₂—, —C(O)—, or —OCH₂—, then Cy² is not optionally substitutedphenyl or naphthyl.
 56. The compound according to claim 54 wherein whenAy² is o-anilinyl optionally substituted by halo, C₁-C₆-alkyl,C₁-C₆-alkoxy or —NO₂, q is 0, Ar² is phenyl, and X¹ is —CH₂—, then Cy²is not substituted pyridone (which substituents of the pyridone are notlimited to substituents described herein).
 57. The compound according toclaim 54 wherein when X¹ is —CH₂—, Ar² is optionally substituted phenyl,q is 1, and R⁶ is H, then Cy² is not optionally substituted imidazole.58. The compound according to claim 54 wherein when Ar² is amino orhydroxy substituted phenyl, X¹ is C₀-C₈-alkyl-X^(1a)—C₀-C₈-alkyl,wherein X^(1a) is —CH₂—, —O—, —S—, —NH—, —C(O)—, then Cy² is notoptionally substituted naphthyl or di- or -tetrahydronaphthalene. 59.The compound according to claim 54 wherein when Ay² is o-phenol, Ar² issubstituted phenyl, X¹ is —O—, —S—, —CH₂—, —O—CH₂—, —S—CH₂—, or —C(O)—,and R⁵ and R⁶ are H, then Cy² is not optionally substituted naphthyl.60. The compound according to claim 54 wherein when Ay² is o-anilinyl, qis 0, Ar² is unsubstituted phenyl, X¹ is —CH₂—, then Cy² is notsubstituted 6-hydroimidazolo[5,4-d]pyridazin-7-one-1-yl or substituted6-hydroimidazolo[5,4-d]pyridazine-7-thione-1-yl.
 61. The compoundaccording to claim 54 wherein Ay² is phenyl or thienyl, each substitutedwith —OH or —NH₂.
 62. The compound according to claim 54 wherein theamino or hydroxy substituent is ortho to the nitrogen to which Ay² isattached.
 63. The compound according to claim 54 wherein Ay² is orthoaniline, ortho phenol, 3-amino-2-thienyl, or 3-hydroxy-2-thienyl. 64.The compound according to claim 54 wherein q is 1; M¹, at eachoccurrence, is selected from the group consisting of —N(R⁷)—, —S—,—C(O)—NH—, and —O—C(O)—NH—, where R⁷ is selected from the groupconsisting of hydrogen, alkyl, aryl, aralkyl, and acyl; and Ay² isanilinyl, which is optionally substituted.
 65. The compound according toclaim 64 wherein the —NH₂ group of Ay² is in an ortho position withrespect to the nitrogen atom to which Ay² is attached.
 66. The compoundaccording to claim 65 wherein R⁵ and R⁶ are independently selected fromthe group consisting of hydrogen and C₁-C₄ alkyl.
 67. The compoundaccording to claim 65 wherein R⁵ and R⁶ are hydrogen.
 68. The compoundaccording to claim 54 wherein Ar² has the formula

and wherein G, at each occurrence, is independently N or C, and C isoptionally substituted.
 69. The compound according to claim 68 whereinAr² has the formula


70. The compound according to claim 54 wherein Ar² is selected from thegroup consisting of phenylene, pyridylene, pyrimidylene, andquinolylene.
 71. The compound according to claim 54 wherein X¹ is achemical bond.
 72. The compound according to claim 54 wherein X¹ isL²—M²—L², and M² is selected from the group consisting of —NH—,—N(CH₃)—, —S—, —C(O)—N(H)—, and —O—C(O)—N(H)—.
 73. The compoundaccording to claim 54 wherein X¹ is L²—M²—L², where at least oneoccurrence of L² is a chemical bond.
 74. The compound according to claim54 wherein X¹ is L²—M²—L², where at least one occurrence of L² isalkylene, preferably methylene.
 75. The compound according to claim 54wherein X¹ is L²—M²—L², where at least one occurrence of L² isalkenylene.
 76. The compound according to claim 54 wherein X¹ isM¹—L²—M¹ and M¹ is selected from the group consisting of —NH—, —N(CH₃)—,—S—, and —C(O)—N(H)—.
 77. The compound according to claim 54 wherein Cy²is aryl or heteroaryl, each optionally substituted.
 78. The compoundaccording to claim 54 wherein Cy² is phenyl, pyridyl, imidazolyl, orquinolyl, each of which is optionally substituted.
 79. The compoundaccording to claim 54 wherein Cy² is heterocyclyl.
 80. The compoundaccording to claim 54 wherein Cy² is

each of which is optionally substituted and is optionally fused to oneor two aryl rings.
 81. The compound according to claim 54 wherein Cy²has from one and three substituents independently selected from thegroup consisting of alkyl, alkoxy, amino, nitro, halo, haloalkyl, andhaloalkoxy.
 82. The compound according to claim 54 wherein thesubstituents are selected from methyl, methoxy, fluoro, trifluoromethyl,trifluoromethoxy, nitro, amino, aminomethyl, and hydroxymethyl
 83. Thecompound of claim 54 of structural formula (2a):

wherein Ar^(a) is phenyl or thienyl; R⁶ is H, or C₁-C₆-alkyl (preferably—CH₃); Y and Z are independently —CH═ or —N═; W is halo,(V′—L⁴)_(t)—V—L³—; L³ is a direct bond, —C₁-C₆-hydrocarbyl,—(C₁-C₃-hydrocarbyl)_(m1)—X′—(C₁-C₃-hydrocarbyl)_(m2),—NH—(C₀-C₃-hydrocarbyl), (C₁-C₃- hydrocarbyl)-NH—, or—NH—(C₁-C₃-hydrocarbyl)-NH—; m1 and m2 are independently 0 or 1; X′ is—N(R²¹)—, —C(O)N(R²¹)—, N(R²¹)C(O)—, —O—, or —S—; R²¹ is —H,V″—(C₁-C₆-hydrocarbyl)_(c); L⁴ is(C₁-C₆-hydrocarbyl)_(a)—M—(C₁-C₆-hydrocarbyl)_(b); a and b areindependently 0 or 1; M is —NH—, —NHC(O)—, —C(O)NH—, —C(O)—, —SO₂—,—NHSO₂—, or —SO₂NH— V, V′, and V″ are independently selected fromcycloalkyl, heterocyclyl, aryl, and heteroaryl; t is 0 or 1; or W, theannular C to which it is bound, and Y together form a monocycliccycloalkyl, heterocyclyl, aryl, or heteroaryl; and wherein the

and Ar^(a) rings are optionally further substituted with from 1 to 3substituents independently selected from methyl, hydroxy, methoxy, halo,and amino.
 84. The compound according to claim 83 wherein: Y and Z are—CH═ and R⁶ is H; W is V—L³; L³ is —NH—CH— or —CH—NH—; V is phenyloptionally substituted with from 1 to 3 moieties independently selectedfrom halo, hydroxy, C₁-C₆-hydrocarbyl, C₁-C₆-hydrocarbyl-oxy or -thio(particularly methoxy or methylthio), wherein each of the hydrocarbylmoieties are optionally substituted with one or more moietiesindependently selected from halo, nitroso, amino, sulfonamido, andcyano; and Ar^(a) is phenyl and the amino moieties to which it is boundare ortho to each other.
 85. The compound according to claim 83 whereinV is an optionally substituted ring moiety selected from:


86. The compound according to claim 83 wherein W is selected from:,

and


87. The compound according to claim 83 wherein the

and Ar^(a) rings are not further substituted.
 88. The compound accordingto claim 83 selected from the following, in which, unless expresslydisplayed otherwise, Ar^(a) is phenyl: Cpd W Y Z R⁶ 481

CH CH H 484

492

CH CH H 493

CH CH H 494

CH CH H 495

CH CH H 496

CH CH H 497

CH CH H 498

CH CH H 499

CH CH H 500

CH CH H 501

CH CH H 502

CH CH H 503

CH CH H 504

CH CH H 505

CH CH H 506

CH CH H 507

CH CH H 508

CH CH H 509

CH CH H 510

CH CH H 511

CH CH H 512

CH N H 516 Br— CH CH CH₃ 517

CH CH CH₃ 518

CH CH CH₃ 519

CH CH H 520

CH CH H 521

N CH H 522

N CH H 523

CH CH H 524

N CH H 525

N CH H 526

CH CH H 527

CH CH H 528

CH CH H 529

CH CH H 530

CH CH H 531

CH CH H 532

CH CH H 533

CH CH H 534

CH CH H 535

CH CH H 536

CH CH H 537

CH CH H 538

CH CH H 539

CH CH H 540

CH CH H 541

CH CH H 542

CH CH H 543

CH CH H 544

CH CH H 545

CH CH H 546

CH CH H 547

CH CH H 548

CH CH H 549

CH CH H 550

CH CH H 551

CH CH H 552

CH CH H 553

CH CH H 554

CH CH H 555

CH CH H 556

CH CH H 557

CH CH H 558

CH CH H 559

CH CH H 560

561

562

CH CH H 563

CH CH H 564

565

CH CH H 566

CH CH H 567

568

569

CH N H 570


89. The compound according to claim 88 wherein the amide nitrogen andthe amino nitrogen bound to Ar^(a) are ortho to each other)
 90. Thecompound according to claim 54, the invention comprises compounds of theformula (2b):

or a pharmaceutically acceptable salt thereof, wherein Ay² is phenyl orthienyl, each substituted at the ortho position with —NH₂ or —OH andeach further optionally substituted with one to three substituentsindependently selected from —NH₂, —OH, and halo; q is 0 or 1; X¹ isselected from CH₂—, —NH—CH₂—, and —S—CH₂—; Cy² is monocyclic or fusedbicyclic aryl or heteroaryl optionally substituted with one to threesubstituents selected from CH₃—, CH₃O—, phenyl optionally substitutedwith one to three CH₃O—, morphylinyl, morphylinyl-C₁-C₃-alkoxy, cyano,and CH₃C(O)NH—; provided that when Cy² is naphthyl, X¹ is —CH₂—, and qis 0 or 1, Ay² is not o-hydroxyphenyl.
 91. The compound according toclaim 90 wherein Ay² is selected from:


92. The compound according to claim 90 wherein Cy² is phenyl, pyridinyl,pyrimidinyl, benzimidazolyl, benzothiazolyl, thienyl,tetrahydroquinozolinyl, or 1,3-dihydroquinazoline-2,4-dione, eachoptionally substituted with one to three CH₃O—.
 93. The compoundaccording to claim 90 wherein Cy² is phenyl substituted with one tothree CH₃O—.
 94. A histone deacetylase inhibitor of formula (3):

or a pharmaceutically acceptable salt thereof, wherein Ar³ is arylene orheteroarylene, either of which is optionally substituted; Cy³ iscycloalkyl, aryl, heteroaryl, or heterocyclyl, each of which isoptionally substituted, and each of which is optionally fused to one ortwo aryl or heteroaryl rings, or to one or two saturated or partiallyunsaturated cycloalkyl or heterocyclic rings, each of which rings isoptionally substituted; provided that when Cy³ is a cyclic moiety having—C(O)—, —C(S)—, —S(O)—, or —S(O)₂— in the ring, then Cy³ is notadditionally substituted with a group comprising an aryl or heteroarylring; and X² is selected from the group consisting of a chemical bond,L³, W¹—L³, L³—W¹, W¹—L³—W¹, and L³—W¹—L³, wherein W¹, at eachoccurrence, is S, O, or N(R⁹), where R⁹ is selected from the groupconsisting of hydrogen, alkyl, aryl, and aralkyl; and L³ is C₁-C₄alkylene, C₂-C₄ alkenylene, or C₂-C₄ alkynylene; provided that X² doesnot comprise a —C(O)—, —C(S)—, —S(O)—, or —S(O)₂— group; and furtherprovided that when Cy³ is pyridine, then X² is L³, W¹—L³, or L³—W¹. 95.The compound according to claim 94 wherein Ar³ has the structure:

wherein Q, at each occurrence, is independently N or C, and C isoptionally substituted;
 96. The compound according to claim 94 whereinX² is selected from the group consisting of L³, W¹—L³, L³—W¹, W¹—L³—W¹,and L³—W¹—L³.
 97. The compound according to claim 94 wherein when X² isa chemical bond, then Ar³ is not

and Cy³ is not the radical of a substituted or unsubstituted diazepineor benzofuran.
 98. The compound according to claim 95 wherein Q at eachoccurrence is C(R⁸), where R⁸ is selected from the group consisting ofhydrogen, alkyl, aryl, aralkyl, alkoxy, amino, nitro, halo, haloalkyl,and haloalkoxy.
 99. The compound according to claim 95 wherein from oneto about three Q are nitrogen.
 100. The compound according to claim 94wherein Ar³ is selected from the group consisting of phenylene,pyridylene, thiazolylene, and quinolylene.
 101. The compound accordingto claim 94 wherein X² is a chemical bond.
 102. The compound accordingto claim 94 wherein X² is a non-cyclic hydrocarbyl.
 103. The compoundaccording to claim 94 wherein X² is alkylene.
 104. The compoundaccording to claim 94 wherein X² methylene or ethylene.
 105. Thecompound according to claim 94 wherein X² alkenylene or alkynylene. 106.The compound according to claim 102 wherein one carbon in thehydrocarbyl chain is replaced with —NH— or —S—.
 107. The compoundaccording to claim 94 wherein X² is W¹—L³—W¹ and W¹ is —NH— or —N(CH₃)—.108. The compound according to claim 94 wherein Cy³ is cycloalkyl. 109.The compound according to claim 94 wherein Cy³ is cyclohexyl.
 110. Thecompound according to claim 94 wherein Cy³ is aryl or heteroaryl, eachof which is optionally substituted and is optionally fused to one or twoaryl rings.
 111. The compound according to claim 94 wherein Cy³ isphenyl, pyridyl, pyrimidyl, imidazolyl, thiazolyl, oxadiazolyl,quinolyl, or fluorenyl, each of which is optionally substituted and isoptionally fused to one or two aryl rings.
 112. The compound accordingto claim 94 wherein the cyclic moiety of Cy³ is fused to a benzene ring.113. The compound according to claim 94 wherein Cy³ has from one tothree substituents independently selected from the group consisting ofalkyl, alkoxy, aryl, aralkyl, amino, halo, haloalkyl, and hydroxyalkyl.114. The compound according to claim 113 wherein the substituents areselected from methyl, methoxy, fluoro, trifluoromethyl, amino, nitro,aminomethyl, hydroxymethyl, and phenyl.
 115. The compound. according toclaim 94 wherein Cy³ has from one to three substituents of the formula—K¹—N(H)(R¹⁰), wherein K¹ is a chemical bond or C₁-C₄ alkylene; R¹⁰ isselected from the group consisting of Z′ and —Ak²—Z′, wherein Ak² isC₁-C₄ alkylene; and Z′ is cycloalkyl, aryl, heteroaryl, or heterocyclyl,each of which is optionally substituted, and each of which is optionallyfused to one or two aryl or heteroaryl rings, or to one or two saturatedor partially unsaturated cycloalkyl or heterocyclic rings.
 116. Thecompound according to claim 115 wherein the substituent is selected from


117. The compound according to claim 94 wherein Cy³ is heterocyclyl,each of which is optionally substituted and is optionally fused to oneor two aryl rings.
 118. The compound according to claim 94 wherein Cy³is selected from


119. The compound according to claim 117 wherein the heterocycle of Cy³is fused to a benzene ring.
 120. The compound of claim 94 wherein whenAr⁴ is quinoxalinylene, then X³ is not —CH(OH)—.
 121. The compound ofclaim 94 wherein Ar³ is

and X is —CH₂—, —NH—, O, or S.
 122. The compound of claim 94 wherein Ar³is

and X is S or O.
 123. The compound according to claim 54 wherein Ay² isortho-anilinyl; q is 0; and X¹ is M¹—L²—M¹ or L²—M²—L².
 124. Thecompound according to claim 123 wherein Ar² is aryl or heteroaryl; andCy²—X¹— is collectively selected from the group consisting of a)A₁—L₁—B₁—, wherein A₁ is an optionally substituted aryl, optionallysubstituted heteroaryl or optionally substituted heterocyclyl; whereinL₁ is —(CH₂)₀₋₁NH(CH₂)₀₋₁—, —NHC(O)—, or —NHCH₂—; and wherein B₁ isphenyl or a covalent bond; b) A₂—L₂—B₂—, wherein A₂ is CH₃(C═CH₂)—,optionally substituted cycloalkyl, optionally substituted alkyl, oroptionally substituted aryl; wherein L₂ is —C≡C—; and wherein B₂ is acovalent bond; c) A₃—L₃—B₃—, wherein A₃ is an optionally substitutedaryl, optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₃ is a covalent bond; and wherein B₃ is —CH₂NH—;d) A₄—L₄—B₄—, wherein A₄ is an optionally substituted aryl; wherein L₄is —NHCH₂—; and wherein B₄ is a thienyl group; e) A₅—L₅—B₅—, wherein A₅is an optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₅ is a covalent bond; and wherein B₅ is —SCH₂—;f) morpholinyl-CH₂— g) optionally substituted aryl; h) A₆—L₆—B₆—,wherein A₆ is an optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl; wherein L₆ is acovalent bond; and wherein B₆ is —NHCH₂—; i) A₇—L₇—B₇—, wherein A₇ is anoptionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₇ is a covalent bond; and wherein B₇ is —CH₂—; j)aptionally substituted heteroaryl or optionally substitutedheterocyclyl; k) A₈L₈—B₈—, wherein A₈ is optionally substituted phenyl;wherein L₈ is a covalent bond; and wherein B₈ is —O—; l) A₉—L₉—B₉—,wherein A₉ is an optionally substituted aryl; wherein L₉ is a covalentbond; and wherein B₉ is a furan group; m) A₁₀—L₁₀—B₁₀—, wherein A₁₀ isan optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁₀ is —CH(CH₂CH₃)—; and wherein B₁₀ is —NHCH₂—;n) A₁₁—L₁₁—B₁₁—, wherein A₁₁ is an optionally substituted heteroaryl oroptionally substituted heterocyclyl; wherein L₁₁ is a covalent bond; andwherein B₁₁ is —OCH₂—; o) A₁₂—L₁₂—B₁₂—, wherein A₁₂ is an optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclyl; wherein L₁₂ is —NHC(O)—; and wherein B₁₂ is—N(optionally substituted aryl)CH₂—; p) A₁₃—L₁₃—B₁₃—, wherein A₁₂ is anoptionally substituted aryl, optionally substituted heteroaryl oroptionally substituted heterocyclyl; wherein L₁₃ is a covalent bond; andwherein B₁₃ is —NHC(O)—; q) A₁₄—L₁₄—B₁₄—, wherein A₁₄ is an optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclyl; wherein L₁₄ is —NHC(O)(optionally substitutedheteroaryl); and wherein B₁₄ is —S—S—; r) F₃CC(O)NH—; s) A₁₅—L₁₅—B₁₅—,wherein A₁₅ is an optionally substituted aryl, optionally substitutedheteroaryl or optionally substituted heterocyclyl; wherein L₁₅ is—CH₂)₀₋₁NH(optionally substituted heteroaryl)-; and wherein B₁₅ is—NHCH₂—; t) A₁₆—L₁₆—B₁₆—, wherein A₁₆ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein L₁₆ is a covalent bond; and wherein B₁₆ is—N(optionally substituted alkyl)CH₂—; and u) A₁₆—L₁₆—B₁₆—, wherein A₁₆is an optionally substituted aryl, optionally substituted heteroaryl oroptionally substituted heterocyclyl; wherein L₁₆ is a covalent bond; andwherein B₁₆ is —(optionally substituted aryl-CH₂)₂—N—.
 125. The compoundaccording to claim 123 wherein Cy²—X¹— is collectively selected from thegroup consisting of a) D₁—E₁—F₁—, wherein D₁ is an optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclyl; wherein E₁ is —CH₂— or a covalent bond; andwherein B₁ is a covalent bond; b) D₂—E₂—F₂—, wherein D₂ is an optionallysubstituted aryl, optionally substituted heteroaryl or optionallysubstituted heterocyclyl; wherein E₂ is —NH(CH₂)₀₋₂—; and wherein F₂ isa covalent bond; c) D₃—E₃—F₃—, wherein D₃ is an optionally substitutedaryl, optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₃ is —(CH₂)₀₋₂NH—; and wherein F₃ is a covalentbond; d) D₄—E₄—F₄—, wherein D₄ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₄ is —S(CH₂)₀₋₂—; and wherein F₄ is a covalentbond; e) D₅—E₅—F₅—, wherein D₅ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E5 is —(CH₂)₀₋₂S—; and wherein F₅ is a covalentbond; and f) D₆—E₆—F₆—, wherein D₆ is an optionally substituted aryl,optionally substituted heteroaryl or optionally substitutedheterocyclyl; wherein E₆ is —NH(CH₂)₀₋₂NH—; and wherein F₆ is a covalentbond.
 126. The compound of claim 54 having formula (3b):

wherein Y and Z are independently N or CH and W is selected from thegroup consisting of:

and


127. The compound according to claim 126 wherein Y, Z and W are one ofthe following combinations: Cpd W Y Z 164

CH CH 165

N CH 166

CH CH 167

CH N 168

CH N 169

CH CH 170

CH CH 171

N CH 172

CH CH 174

CH N 175

CH N 176

CH N 177

CH CH 178

N CH 179

CH CH 180

CH CH 181

CH CH 182

CH CH and 183

CH CH


128. The compound according to claim 126 wherein Y, Z and W are one ofthe following combinations: Cpd W Y Z 187

CH CH 188

CH CH 189

CH CH 190

CH CH 193

CH CH 194

CH CH 195

CH CH 196

CH CH 320

CH CH 321

CH CH 322

CH CH 323

CH CH 325

CH CH 326

CH CH 327

CH CH 328

CH CH 329

CH CH 330

CH CH 331

CH CH 332

CH CH 333

CH CH 334

CH CH 335

CH CH 336

CH CH 337

CH CH 338

CH CH 339

CH CH 340

CH CH 341

CH CH 342

CH CH 343

CH CH 344

CH CH 345

CH CH 346

CH CH 347

CH CH 348

CH CH 349

CH CH 350

CH CH 351

CH CH 352

CH CH 353

CH CH 354

CH CH 355

CH CH 356

CH CH 357

CH CH 358

CH CH 359

CH CH 360

CH CH 361

CH CH 362

CH CH 363

CH CH 364

CH CH 365

CH CH 366

CH CH 367

CH CH 368

CH CH 369

CH CH 370

CH CH 371

CH CH 372

CH CH 373

CH CH 374

CH CH 375

CH CH 377

CH CH 378

CH CH 379

CH CH 380

N CH 381

CH CH 382

CH CH 383

CH CH 384

CH CH 385

CH CH 386

CH CH 387

CH CH 388

CH CH 389

CH CH 390

CH CH 391

CH CH 392

CH CH 393

CH CH 394

CH CH 395

CH CH 396

CH CH 397

CH CH 398

CH N 399

CH CH 400

CH CH 401

CH CH 402

CH CH 403

CH CH 404

CH CH 405

CH CH 406

CH CH 407

CH CH 408

CH CH 409

CH CH 410

CH CH 411

CH CH 412

CH CH 413

CH CH 414

CH CH 415

CH CH 416

CH CH 417

CH CH 418

CH CH 419

CH CH 420

CH CH 421

CH CH 422

CH CH 423

CH CH 424b

CH CH 425

CH CH 426

CH CH 427

CH CH 428

CH CH 429

CH CH 430

CH CH 431

CH CH 432

CH CH 433

CH CH 434

CH CH 435

CH CH 436

CH CH 437

CH CH 438

CH CH 439

CH CH 440

CH CH 441

CH CH 442

CH CH 443

CH CH 444

CH CH 445

CH N 446

CH N 447

CH CH 448

CH CH 449

CH CH 450

CH CH 451

CH CH 452

CH CH 453

454

455

CH CH 456

CH CH 457

458

CH CH 459

CH CH 460

CH N 461

CH CH 462

CH CH 463

N CH 464

N CH 465

CH CH 466

CH CH 467

CH CH 468

CH CH


129. A compound selected from the group consisting of the following andtheir pharmaceutically acceptable salts:


130. A histone deacetylase inhibitor selected from the compounds listedin Tables 2a-b, 3a-d, 4a-c, and 5a-5f, or a pharmaceutically acceptablesalt thereof.
 131. A composition comprising a compound according to anyone of claim 1-130 and a pharmaceutically acceptable carrier.
 132. Amethod of inhibiting histone deacetylase in a cell, the methodcomprising contacting a cell with a compound according to any one ofclaim 1-130.